Method for producing purified recombinant Haemophilus influenzae transferrin binding proteins

ABSTRACT

Purified and isolated nucleic acid is provided which encodes a transferrin receptor protein of a strain of Haemophilus or a fragment or an analog of the transferrin receptor protein. The nucleic acid sequence may be used to produce peptides free of contaminants derived from bacteria normally containing the Tbp1 or Tbp2 proteins for purposes of diagnostics and medical treatment. Furthermore, the nucleic acid molecule may be used in the diagnosis of infection. Also provided are recombinant Tbp1 or Tbp2 and methods for purification of the same. Live vectors expressing epitopes of transferrin receptor protein for vaccination are provided.

REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 08/337,483,filed Nov. 8, 1994; which is a continuation-in-part of application Ser.No. 08/175,116, filed Dec. 29, 1993, now abandoned; which is acontinuation-in-part of application Ser. No. 08/148,968, filed Nov. 8,1993, now abandoned.

FIELD OF INVENTION

The present invention is related to the molecular cloning of genesencoding transferrin receptor and in particular to the cloning oftransferrin receptor genes from Haemophilus influenzae.

BACKGROUND OF THE INVENTION

Encapsulated Haemophilus influenzae type b strains are the major causeof bacterial meningitis and other invasive infections in young children.However, the non-encapsulated or non-typable H. influenzae (NTHi) areresponsible for a wide range of human diseases including otitis media,epiglottitis, pneumonia, and tracheobronchitis. Vaccines based upon H.influenzae type b capsular polysaccharide conjugated to diphtheriatoxoid (Berkowitz et al., 1987. Throughout this application, variousreferences are referred to in parenthesis to more fully describe thestate of the art to which this invention pertains. Full bibliographicinformation for each citation is found at the end of the specification,immediately preceding the claims. The disclosures of these referencesare hereby incorporated by reference into the present disclosure),tetanus toxoid (Classon et al., 1989 and U.S. Pat. No. 4,496,538), orNeisseria meningitidis outer membrane protein (Black et al., 1991) havebeen effective in reducing H. influenzae type b-induced meningitis, butnot NTHi-induced disease (Bluestone, 1982).

Otitis media is the most common illness of early childhood with 60-70%of all children of less than 2 years of age experiencing between one andthree ear infections. Chronic otitis media is responsible for hearing,speech and cognitive impairments in children. H. influenzae infectionsaccount for about 30% of the cases of acute otitis media and about 60%of chronic otitis media. In the United States alone, treatment of otitismedia costs between 1 and 2 billion dollars per year for antibiotics andsurgical procedures such as tonsillectomies, adenoidectomies andinsertion of tympanostomy tubes. Furthermore, many of the causativeorganisms of otitis media are becoming resistant to antibiotictreatment. An effective prophylactic vaccine against otitis media isthus desirable. Non-typable strains of H. influenzae are also importantpathogens responsible for pneumonia in the elderly and other individualswho are particularly susceptible to respiratory infections. There isthus a need for antigens from H. influenzae which are useful ascomponents in immunogenic preparations that provide protection againstthe many serotypes of H. influenzae.

Iron is an essential nutrient for the growth of many bacteria. Severalhuman pathogens, such as H. influenzae, Branhamella catarrhalis, N.meningitidis, N. gonorrhoeae and non-pathogenic commensal Neisseriastrains, can utilize human transferrin as an iron source (Schryvers,1988; Schryvers and Lee, 1989; Mickelsen and Sparling, 1981). Thebacterial transferrin receptor (TfR) is composed of two chains, Tbp1 andTbp2. In strains of H. influenzae, the molecular weight of Tbp1 isapproximately 100,000, whereas the molecular weight of Tbp2 is variable,ranging from 60,000 to 90,000, depending upon the strain (Schryvers andGray-Owen, 1992; Holland et al., 1992). Expression of H. influenzaetransferrin receptor is thought to be iron-and/or hemin-regulated(Morton et al., 1993) and a putative fur-binding site (Braun and Hantke,1991) has been identified upstream of tbp2. This sequence is found inthe promoter region of genes which are negatively regulated by iron,including N. meningitidis TfR (Legrain et al., 1993). The promoter isfollowed by the tbp2 and tbp1 genes, an arrangement found in otherbacterial TfR operons (Legrain et al, 1993; Wilton et al., 1993).Antibodies which block the access of the transferrin receptor to itsiron source may prevent bacterial growth. In addition, antibodiesagainst TfR that are opsonizing or bactericidal may also provideprotection by alternative mechanisms. Thus, the transferrin receptor,fragments thereof, its constituent chains, or peptides derived therefromare vaccine candidates to protect against H. influenzae disease. Miceimmunized with N. meningitidis TfR proteins in Freund's adjuvant wereprotected from homologous challenge and the anti-TfR antisera werebactericidal and protective in a passive transfer assay (Danve et al.,1993). Pigs immunized with recombinant A. pleuropneumoniae Tbp2 wereprotected against homologous challenge but not heterologous challenge(Rossi-Campos et al., 1992). These data indicate the efficacy ofTfR-based vaccines in protection from disease. It would be desirable toprovide the sequence of the DNA molecule that encodes transferrinreceptor and peptides corresponding to portions of the transferrinreceptor and vectors containing such sequences for diagnosis,immunization and the generation of diagnostic and immunologicalreagents.

Poliovirus is an enterovirus, a genus of the family Picornaviridae.There are three distinct serotypes of the virus, and multiple strainswithin each serotype. Virulent strains are causative agents of paralyticpoliomyelitis. Attenuated strains, which have reduced potential to causeparalytic disease, and inactivated virulent strains, are used asvaccines. Infection with the virus induces long-lasting, protective,mucosal immunity. Inoculation with inactivated poliovirus vaccines canalso induce a mucosal immune response.

The structure of poliovirus is known, and is highly conserved amongstrains and serotypes. The structures of several other picornaviruses(viruses belonging to genera of the family Picornaviridae) have alsobeen determined, and have been shown to be closely related to thestructure of poliovirus. It is possible to express foreign epitopes onthe capsid of polioviruses (Murdin et al, 1992) and this work has beenextended to other picornaviruses. Epitopes which have been expressed areusually short, well defined, contiguous epitopes, and most have beenexpressed within poliovirus neutralisation antigenic site I (NAgI) orthe equivalent site on other picornaviruses. This site includes the looplinking beta strands B and C (the BC loop) of poliovirus capsid proteinVP1. The BC loop of VP1 is a surface-exposed loop of nine amino acidswhich can be replaced and extended with at least twenty-fiveheterologous amino acids (Murdin et al, 1991). Hybrid or chimericpolioviruses expressing transferrin receptor epitopes, which grow to ahigh titre and are immunogenic, would be useful as vaccines and as toolsfor the generation of immunological reagents.

SUMMARY OF THE INVENTION

The present invention is directed towards the provision of purified andisolated nucleic acid molecules encoding a transferrin receptor of astrain of Haemophilus or a fragment or an analog of the transferrinreceptor protein. The nucleic acid molecules provided herein are usefulfor the specific detection of strains of Haemophilus, and for diagnosisof infection by Haemophilus. The purified and isolated nucleic acidmolecules provided herein, such as DNA, are also useful for expressingthe TfR genes by recombinant DNA means for providing, in an economicalmanner, purified and isolated transferrin receptor subunits, fragmentsor analogs thereof. The transferrin receptor, subunits or fragmentsthereof or analogs thereof, as well as nucleic acid molecules encodingthe same and vectors containing such nucleic acid molecules, are usefulin immunogenic compositions against diseases caused by Haemophilus, thediagnosis of infection by Haemophilus and as tools for the generation ofimmunological reagents. Monoclonal antibodies or mono-specific antisera(antibodies) raised against the transferrin receptor protein produced inaccordance with aspects of the present invention are useful for thediagnosis of infection by Haemophilus, the specific detection ofHaemophilus (in for example in vitro and in vivo assays) and for thetreatment of diseases caused by Haemophilus.

Peptides corresponding to portions of the transferrin receptor oranalogs thereof are useful immunogenic compositions against diseasecaused by Haemophilus, the diagnosis of infection by Haemophilus and astools for the generation of immunological reagents. Monoclonalantibodies or antisera raised against these peptides, produced inaccordance with aspects of the present invention, are useful for thediagnosis of infection by Haemophilus, the specific detection ofHaemophilus (in, for example, in vitro and in vivo assays) and for usein passive immunization as a treatment of disease caused by Haemophilus.

In accordance with one aspect of the present invention, there isprovided a purified and isolated nucleic acid molecule encoding atransferrin receptor protein of a strain of Haemophilus, moreparticularly, a strain of H. influenzae, specifically a strain of H.influenzae type b, such as H. influenzae type b strain DL63, Eagan orMinnA, or a non-typable strain of H. influenzae, such as H. influenzaestrain PAK12085, SB33, SB12, SB29, SB30 or SB32, or a fragment or ananalog of the transferrin receptor protein.

In one preferred embodiment of the invention, the nucleic acid moleculemay encode only the Tbp1 protein of the Haemophilus strain or only theTbp2 protein of the Haemophilus strain. In another preferred embodimentof the invention, the nucleic acid may encode a fragment of thetransferrin receptor protein of a strain of Haemophilus having aconserved amino acid sequence which is conserved among bacteria thatproduce transferrin receptor protein. Such conserved amino acid sequencemay have an amino acid sequence contained within the amino acid sequenceof the peptides shown in Tables 2 and 3 below for Haemophilus influenzaetype b strain Eagan as well as corresponding peptides of other strainsof Haemophilus influenzae.

In another aspect of the present invention, there is provided a purifiedand isolated nucleic acid molecule having a DNA sequence selected fromthe group consisting of (a) any one of the DNA sequences set out inFIGS. 3, 4, 5, 6, 7, 8, 9, 10 or 11 (SEQ ID NOS: 1, 2, 3, 4, 105, 108,110, 112, 114) or the complementary DNA sequence of any one of saidsequences; (b) a DNA sequence encoding one of the amino acid sequencesset out in FIG. 3, 4, 5, 6, 7, 8, 9, 10 or 11 (SEQ ID NOS: 5, 6, 7, 8,9, 10, 11, 12, 106, 107, 109, 111, 113, 115) or the complementary DNAsequence thereto; and (c) a DNA sequence which hybridizes understringent conditions to any one of the DNA sequences defined in (a) or(b). The DNA sequence defined in (c) preferably has at least about 90%sequence identity with any one of the DNA sequences defined in (a) and(b).

In an additional aspect, the present invention includes a vector adaptedfor transformation of a host, comprising a nucleic acid molecule asprovided herein. The vector may be one having the characteristics ofplasmid DS-712-1-3 having ATCC accession number 75603 or plasmidJB-1042-7-6 having ATCC accession number 75607.

The plasmids may be adapted for expression of the encoded transferrinreceptor, fragments or analogs thereof, in a heterologous or homologoushost, in either a lipidated or non-lipidated form. Accordingly, afurther aspect of the present invention provides an expression vectoradapted for transformation of a host comprising a nucleic acid moleculeas provided herein and expression means operatively coupled to thenucleic acid molecule for expression by the host of the transferrinreceptor protein or the fragment or analog of the transferrin receptorprotein. In specific embodiments of this aspect of the invention, thenucleic acid molecule may encode substantially all the transferrinreceptor protein, only the Tbp1 protein or only the Tbp2 protein of theHaemophilus strain. The expression means may include a nucleic acidportion encoding a leader sequence for secretion from the host of thetransferrin receptor protein or the fragment or the analog of thetransferrin receptor protein. The expression means also may include anucleic acid portion encoding a lipidation signal for expression fromthe host of a lipidated form of the transferrin receptor protein or thefragment or the analog of the transferrin receptor protein. Theexpression plasmid may have the identifying characteristics of plasmidJB-1468-29, JB-1600-1 or JB-1424-2-8. The host may be selected from, forexample, Escherichia coli, Bacillus, Haemophilus, fungi, yeast orbaculovirus and Semliki Forest virus expression systems may be used.

In an additional aspect of the invention, there is provided atransformed host containing an expression vector as provided herein.Such host may selected from JB-1476-2-1, JB-1437-4-1 and JB-1607-1-1.The invention further includes a recombinant transferrin receptorprotein or fragment or analog thereof producible by the transformedhost.

As described in more detail below, there has been produced Tbp1 and Tbp2protein receptors separate from each other. Further aspects of thepresent invention, therefore, provide an isolated and purified Tbp1protein of a strain of Haemophilus free from the Tbp2 protein of theHaemophilus strain and an isolated and purified Tbp2 protein of a strainof Haemophilus free from the Tbp1 protein of the Haemophilus strain. TheHaemophilus strain may be H. influenzae type b or a non-typable strainof H. influenzae.

The present invention further provides synthetic peptides correspondingto portions of the transferrin receptor. Accordingly, in a furtheraspect of the invention, there is provided a synthetic peptide having noless than six amino acids and no more than 150 amino acids andcontaining an amino acid sequence corresponding to a portion only of atransferrin receptor protein of a strain of bacteria or of an analog thetransferrin receptor protein. The bacterial strain preferably is aHaemophilus strain, particularly a H. influenzae strain, specifically astrain of H. influenzae type b or a non-typable strain of H. influenzae.

The peptides provided herein may comprise an amino acid sequence whichis conserved among bacteria that produces transferrin receptor protein,including strains of Haemophilus. The peptide may include an amino acidsequence LEGGFYGP (SEQ ID NO: 74) or LEGGFYG (SEQ ID NO: 85). Thepeptides provided herein may have an amino acid sequence selected fromthose presented in Table 2 or 3 below for the Eagan strain of H.influenzae type b and corresponding amino acid sequences for otherstrains of H. influenzae.

In accordance with another aspect of the invention, an immunogeniccomposition is provided which comprises at least one active componentselected from at least one nucleic acid molecule as provided herein, atleast one recombinant protein as provided herein, at least one of thepurified and isolated Tbp1 or Tbp2 proteins, as provided herein, atleast one synthetic peptide, as provided herein, and a live vector, asprovided herein, and a pharmaceutically acceptable carrier therefor orvector therefor. The at least one active component produces an immuneresponse when administered to a host.

The immunogenic compositions provided herein may be formulated as avaccine for in vivo administration to protect against diseases caused bybacterial pathogens that produce transferrin receptors. For suchpurpose, the compositions may be formulated as a microparticle, capsuleor liposome preparation. Alternatively, the compositions may be providedin combination with a targeting molecule for delivery to specific cellsof the immune system or to mucosal surfaces. The immunogenic compositionmay comprise a plurality of active components to provide protectionagainst disease caused by a plurality of species of transferrin receptorproducing bacteria. The immunogenic compositions may further comprise anadjuvant.

In accordance with another aspect of the invention, there is provided amethod for inducing protection against infection or disease caused byHaemophilus or other bacteria that produce transferrin receptor protein,comprising the step of administering to a susceptible host, such as ahuman, an effective amount of the immunogenic composition as recitedabove.

In accordance with another aspect of the invention, an antiserum orantibody specific for the recombinant protein, the isolated and purifiedTbp1 protein or Tbp2 protein, synthetic peptide or the immunogeniccomposition, is provided.

In a further aspect, there is provided a live vector for delivery oftransferrin receptor to a host, comprising a vector containing thenucleic acid molecule as described above. The vector may be selectedfrom Salmonella, BCG, adenovirus, poxvirus, vaccinia and poliovirus. Thevector may specifically be poliovirus and the nucleic acid molecule maycode for a fragment of transferrin receptor having an amino acidsequence of LEGGFYGP (SEQ ID NO: 74) or LEGGFYG (SEQ ID NO: 85). Thepresent invention further includes a plasmid vector having theidentifying characteristics of pT7TBP2A, pT7TBP2B, pT7TBP2C or pT7TBP2D(ATCC designation Nos. 75931, 75932, 75933, 75934).

An additional aspect of the invention provides a strain of Haemophilusthat does not produce transferrin receptor protein. Such strain maycomprise a gene encoding transferrin receptor which is functionallydisabled, such as by insertional mutagenesis. The Haemophilus strain maybe one that has been attenuated and the attenuated strain may comprisethe vector for delivery of transferrin receptor.

As mentioned above, one aspect of the invention provides novel Tbp1 orTbp2 protein of a strain of Haemophilus, preferably a strain ofHaemophilus influenzae, which is isolated and purified and free from theother. A yet further aspect of the present invention provides a methodfor producing such proteins. Accordingly, in this yet further aspect,the present invention provides a method of producing an isolated andpurified Tbp1 or Tbp2 protein of a strain of Haemophilus, comprising thesteps of (a) providing a recombinant host expressing, in inclusionbodies, Tbp1 or Tbp2 protein, but not both; (b) growing the host toprovide a cell mass; (c) disrupting the cell mass to provide a celllysate; (d) fractionating the cell lysate to provide a first supernatantand a first pellet, the first supernatant comprising substantially alarge proportion of soluble host proteins; (e) separating the firstsupernatant from the first pellet; (f) selectively extracting the firstpellet to remove substantially all soluble host proteins and hostmembrane proteins therefrom to provide a second supernatant and anextracted pellet containing the inclusion bodies; (g) separating thesecond supernatant from the extracted pellet; (h) solubilizing theextracted pellet to provide a solubilized extract; and (i) fractionatingthe solubilized extract to provide a Tbp1 or Tbp2 protein containingfraction.

The cell lysate may be fractionated to provide the first supernatant andfirst pellet may be effected by at least one detergent extraction.

The solubilized extract may be fractionated by gel filtration to providethe Tbp1 or Tbp2 protein containing fraction, which may be subsequentlydialyzed to remove at least the detergent and provide a further purifiedsolution of Tbp1 or Tbp2 protein.

BRIEF DESCRIPTION OF DRAWINGS

The present invention will be further understood from the followingdescription with reference to the drawings, in which:

FIG. 1A shows the restriction map of two plasmid clones (pBHT1 andpBHT2) of the transferrin receptor operon of Haemophilus influenzae typeb strain DL63.

FIG. 1B shows the restriction map of clones S-4368-3-3 and JB-901-5-3containing TfR genes from H. influenzae type b strain Eagan.

FIG. 1C shows the restriction map of clone DS-712-1-3 containing thetransferrin receptor gene from H. influenzae type b strain MinnA.

FIG. 1D shows the restriction map of clone JB-1042-7-6 containing thetransferrin receptor gene from the non-typable H. influenzae strain PAK12085.

FIG. 2 illustrates the organization and restriction maps of the clonedTbp1 and Tbp2 genes of identified strains and the genetic organizationof the TfR operon with two genes (tbp1 and tbp2) in tandem forming anoperon under the transcriptional regulation of a single promoter andalso depicts the 3.0 kb DNA fragment of pBHIT2 used to probe librariesfor TfR genes from the Haemophilus strains.

FIGS. 3A to 3Q show the nucleotide sequences of the transferrin receptorgenes (SEQ ID NO: 1) and their deduced amino acid sequences (SEQ ID NO:5--Tbp1 and SEQ ID NO: 6--Tbp2) from H. influenzae type b, strain DL63.The underlined amino acid sequences correspond to peptides of Tbp1identified by amino acid sequencing. The putative signal sequences areindicated by double overlining and correspond to residues 1 to 17 forTbp1 and 1 to 25 for Tbp2.

FIGS. 4A to 4Q show the nucleotide sequences of the transferrin receptorgenes (SEQ ID NO: 2) and their deduced amino acid sequences (SEQ ID NO:7--Tbp1 and SEQ ID NO: 8--Tbp2) from H. influenzae type b strain Eagan.Putative -35, -10 and ribosomal binding site sequences are overlined.

FIGS. 5A to 5Q show the nucleotide sequences of the transferrin receptorgenes (SEQ ID NO: 3) and their deduced amino acid sequences (SEQ ID NO:9--Tbp1 and SEQ ID NO: 10--Tbp2) from H. influenzae type b strain MinnA.Putative -35, -10 and ribosomal binding site sequences are overlined.

FIGS. 6A to 6Q show the nucleotide sequences of the transferrin receptorgenes (SEQ ID NO: 4) and their deduced amino acid sequences (SEQ ID NO.11--Tbp1 and SEQ ID NO. 12--Tbp2) from the non-typable H. influenzaestrain PAK 12085. Putative -35, -10 and ribosomal binding site sequencesare overlined.

FIGS. 7A to 7N show the nucleotide sequences of the transferrin receptorgenes (SEQ ID NO: 105) and their deduced amino acid sequences (SEQ IDNO. 106--Tbp1 and SEQ ID NO. 107--Tbp2) from the non-typable H.influenzae strain SB33.

FIGS. 8A to 8G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO:108) and the deduced amino acid sequence (SEQ ID NO: 109--Tbp2) fromnon-typable strain H. influenzae strain SB12.

FIGS. 9A to 9G show the nucleotide sequence of the Tbp2 gene (SEQ ID NO:110) and the deduced amino acid sequence (SEQ ID NO: 111--Tbp2) fromnon-typable strain H. influenzae strain SB29.

FIGS. 10A to 10G show the nucleotide sequence of the Tbp2 gene (SEQ IDNO: 112) and the deduced amino acid sequence (SEQ ID NO: 113--Tbp2) fromnon-typable strain H. influenzae strain SB30.

FIGS. 11A to 11G show the nucleotide sequence of the Tbp2 gene (SEQ IDNO: 114) and the deduced amino acid sequence (SEQ ID NO: 115--Tbp2) fromnon-typable strain H. influenzae strain SB32.

FIG. 12A shows the nucleotide sequences of the promoter regions and5'-end of the tbp2 genes from H. influenzae strains Eagan (SEQ ID NO:116), MinnA (SEQ ID NO: 117), PAK 12085 (SEQ ID NO: 118) and SB33 (SEQID NO: 119). The coding strand primer used to amplify tbp2 genes by PCRis underlined (SEQ ID NO: 120).

FIG. 12B shows the nucleotide sequence of the intergenic region and5'-end of the tbp1 genes from H. influenzae strains Eagan (SEQ ID NO:121), MinnA (SEQ ID NO: 122), DL63 (SEQ ID NO: 123), PAK 12085 (SEQ IDNO: 124), SB12 (SEQ ID NO: 125), SB29 (SEQ ID NO: 126), SB30 (SEQ ID NO:127), and SB32 (SEQ ID NO: 128). The non-coding strand primer used toamplify the tbp2 genes by PCR is underlined (SEQ ID NO: 129).

FIG. 13 shows the agarose gel analysis of PCR amplified tbp2 genes fromnon-typable H. influenzae strains SB12, SB29, SB30, SB32 and SB33. Lane1 is SB33, lane 2 is SB12, lane 3 is SB29, lane 4 is SB30, lane 5 isSB32.

FIGS. 14A to 14C show a comparison of the amino acid sequences of Tbp1from H. influenzae strains Eagan, DL63, PAK 12085 and SB33 (SEQ ID NOS:7, 5, 11 and 106), N. meningitidis strains B16B6 and M982 (SEQ ID NOS:94 and 95), and N. gonorrhoeae strain FA19 (SEQ ID NO: 96).

FIGS. 15A to 15D show a comparison of the amino acid sequence of Tbp2from H. influenzae strains Eagan, DL63, PAK 12085, SB12, SB29, SB30 andSB32 (SEQ ID NOS: 8, 6, 12, 109, 110, 112, 114), N. meningitidis strainsB16B6 and M982 (SEQ ID NOS: 97 and 98), N. gonorrhoeae strain FA19, andActinobacillus pleuropneumoniae strains AP205 and AP37 (SEQ ID NOS: 99and 100).

FIGS. 16A' and 16A" show the predicted secondary structure of H.influenzae Tbp1 protein and FIGS. 16B' and 16B" show the predictedsecondary structure of H. influenzae Tbp2 protein.

FIG. 17 shows the construction scheme of plasmid JB-1468-29 whichexpresses H. influenzae type b Eagan Tbp1 from E. coli.

FIG. 18 shows the construction scheme of plasmid JB-1424-2-8 whichexpresses H. influenzae type b Eagan Tbp2 from E. coli.

FIG. 19 shows the oligonucleotide pairs (SEQ ID NOS: 130, 131) used toconstruct plasmid JB-1424-2-8.

FIGS. 20A and 20B show the sequence of oligonucleotide pairs A (SEQ IDNOS: 86, 87), B (SEQ ID NOS: 88, 89), C (SEQ ID NOS: 90, 91) and D (SEQID NOS: 92, 93) for constructing Tbp1 and Tbp2 expression plasmids.

FIG. 21 shows the construction scheme of plasmid JB-1600-1 whichexpresses H. influenzae strain SB12 Tbp2 from E. coli.

FIG. 22 shows SDS-PAGE gels of products from the expression ofHaemophilus type b Eagan Tbp1 protein, Eagan Tbp2 protein, andnon-typable H. influenzae SB12 Tbp2 protein from E. coli. Lane 1,JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4 hinduction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) att_(o) ; lane 5, JB-1437-4-1 at t=4 h induction; lane 6, JB-1607-1-1(T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4 h induction.

FIG. 23 shows a purification scheme for recombinant Tbp1 and Tbp2expressed from E. coli.

FIGS. 24, comprising Panels A and B, shows an analysis of the purity ofrecombinant Tbp1 (Panel A) and Tbp2 (Panel B) purified by the scheme ofFIG. 23. Lane 1 contains molecular weight size markers (106, 80, 49.5,32.5, 27.5 and 18.5 kDa), Lane 2 is E. coli whole cell lysate. Lane 3 issolubilized inclusion bodies. Lane 4 is purified Tbp1 or Tbp2.

FIGS. 25A and 25B show the immunogenicity of rTbp1 (upper panel) andrTbp2 (lower panel) in mice.

FIG. 26 shows the reactivity of anti-Eagan rTbp1 antisera with variousH. influenzae strains on a Western blot. Lane 1, BL21/DE3; lane 2, SB12-EDDA; lane 3, SB12 +EDDA; lane 4, SB29 -EDDA; lane 5, SB29 +EDDA; lane6, SB33 -EDDA; lane 7, SB33 +EDDA; lane 8, Eagan -EDDA; lane 9, Eagan+EDDA; lane 10, B. catarrhalis 4223 -EDDA; lane 11, B. catarrhalis 4223+EDDA; lane 12, N. meningitidis 608 -EDDA; lane 13, N. meningitidis 608+EDDA; lane 14, induced JB-1476-2-1 expressing recombinant Eagan Tbp1;lane 15, molecular weight markers. Specific ˜95 kDa bands reacted withthe anti-Tbp1 antisera in lanes 3, 4, 5, 7, 8 and 9, corresponding to H.influenzae strains SB12 SB29 SB33 and ˜110 kDa bands in lanes 10 and 11,corresponding to B. catarrhalis strain 4223; and ˜80 kDa bands in lanes12 and 13, corresponding to N. meningitidis 608.

FIG. 27 shows the reactivity of anti-Eagan rTbp2 antisera with variousH. influenzae strains on a Western blots. Lane 1, molecular weightmarkers; lane 2, induced JB-1437-4-1 expressing recombinant Eagan Tbp2;lane 3, SB12 -EDDA; lane 4, SB12 +EDDA; lane 5, SB29 -EDDA; lane 6, SB29+EDDA; lane 7, SB30 -EDDA; lane 8, SB30 +EDDA; lane 9, SB32 -EDDA; lane10, SB33 -EDDA; lane 11, SB33 +EDDA; lane 12, PAK -EDDA; lane 13, PAK+EDDA; lane 14, Eagan -EDDA; lane 15, Eagan +EDDA. Specific bands of60-70 kDa were reactive with the anti-Tbp2 antisera in lanes, 3, 6, 7,8, 13, 14 and 15, i.e. strains SB12, SB29, SB30, PAK and Eagan.

FIG. 28 shows the construction of plasmids pUHIT1KFH and pUHIT1KFP usedto generate strains of H. influenzae that do not produce transferrinreceptor.

FIG. 29 shows the construction of plasmids encoding chimericpolioviruses expressing an epitope derived from transferrin receptorprotein that is conserved among bacteria that produce transferrinreceptor protein.

FIG. 30, comprising Panels A, B and C, is a Western blot showing thereactivity of antisera produced by immunization of rabbits withpoliovirus chimeras expressing an epitope derived from transferrinreceptor protein that is conserved among bacteria that producetransferrin receptor protein. Panel A shows a Coomassie BrilliantBlue-stained gel showing purified recombinant Tbp2 from H. influenzaestrain SB12 expressed in E. coli (lane 1), purified Tbp2 fromBranhamella catarrhalis strain 4223 (lane 2), a whole cell lysate ofiron-limited B. catarrhalis strain 4223 (lane 3), a whole cell lysate ofE. coli JM109 grown under non-iron limited conditions (lane 5). Panel Bshows results of a Western blot of a replicate gel using a pool of thesera collected on day 27 from rabbits immunised with PV1TBP2A (rabbits40, 41 and 42). Panel C shows the results for a pool of prebleed serafrom the same, which displayed minimal specific reactivity.

In some of the above Figures, the following abbreviations have been usedto designate particular site specific restriction endonucleases: R, EcoRI; Ps, Pst I; H, Hind III; Bg, Bgl II; Nde, Nde I; Ear, Ear I; and Sau,Sau3A I.

In FIG. 28, the following abbreviations have been used to designateparticular site specific restriction endonucleases: A, Acc I; B BamHI;E, Eco RI; O, Xho I; H, Hind III; Ps, Pst I; V, Eco RV; X, Xba I, G, BglII; S, Sal I; K, Kpn I; and S*, Sac I.

GENERAL DESCRIPTION OF THE INVENTION

Any Haemophilus strain may be conveniently used to provide the purifiedand isolated nucleic acid which may be in the form of DNA molecules,comprising at least a portion of the nucleic acid coding for atransferrin receptor as typified by embodiments of the presentinvention. Such strains are generally available from clinical sourcesand from bacterial culture collections, such as the American TypeCulture Collection.

According to an aspect of the invention, the transferrin receptorprotein may be isolated from Haemophilus strains by the methodsdescribed by Schryvers (1989), Ogunnaviwo and Schryvers (1992) and U.S.Pat. No. 5,141,743, the subject matter of which is hereby incorporatedby reference. Although the details of an appropriate process areprovided in patent U.S. Pat. No. 5,141,743, a brief summary of suchprocess is as follows. Isolation of transferrin receptor is achieved byisolating a membrane fraction from a bacterial strain expressingtransferrin binding activity and purifying the transferrin receptor byan affinity method involving the sequential steps of prebinding oftransferrin to the transferrin receptor in the membrane fraction,solubilising the membrane, immobilising the transferrin and separatingthe transferrin receptor from the immobilised transferrin.Alternatively, the receptor proteins may be isolated by a modificationof the above method in which the prebinding step is avoided and a highconcentration of salt is included in the solubilization buffer to allowdirect isolation with immobilized transferrin as described in Ogunnariwoand Schryvers (1992).

In this application, the term "transferrin receptor" is used to define afamily of Tbp1 and/or Tbp2 proteins which includes those havingvariations in their amino acid sequences including those naturallyoccurring in various strains of, for example, Haemophilus. Otherbacterial sources of transferrin receptor include, but are not limitedto, species of Neisseria, Branhamella, Pasteurella and Actinobacillus.Some, if not all, of these bacteria contain both Tbp1 and Tbp2. Thepurified and isolated DNA molecules comprising at least a portion codingfor transferrin receptor of the present invention also include thoseencoding functional analogs of transferrin receptor. In thisapplication, a first protein or peptide is a "functional analog" of asecond protein if the first protein is immunologically related to and/orhas the same function as the second protein or peptide. The functionalanalog may be, for example, a fragment of the protein or a substitution,addition or deletion mutant thereof.

In one particular embodiment, the transferrin receptor was isolated fromH. influenzae type b strain DL63 and purified by affinity chromatographymethods, as described by Schryvers (1989), Ogunnariwo and Schryvers(1992) and in U.S. Pat. No. 5,141,743. The isolated and purifiedtransferrin receptor was used to generate anti-TfR antisera in rabbits.Chromosomal DNA from H. influenzae type b strain DL63 was mechanicallysheared, EcoRI linkers added, and a λZAP expression library constructed.The library was screened with the anti-TfR rabbit antisera and twopositive clones (pBHIT1 and pBHIT2) were obtained which had overlappingrestriction maps (FIG. 1A and FIG. 2). The clones were sequenced and twolarge open reading frames were identified (FIG. 2). The nucleotidesequences of the transferrin receptor genes Tbp1 and Tbp2 (SEQ ID NO: 1)from H. influenzae DL63 and their deduced amino acid sequences (SEQ IDNO: 5--Tbp1 and SEQ ID NO: 6--Tbp2) are shown in FIG. 3. The sequenceanalysis showed the TfR operon to consist of two genes (Tbp1 and Tbp2)arranged in tandem and transcribed from a single promoter (asparticularly shown in FIG. 2 and FIG. 3). The Tbp2 protein tends to varyin molecular weight depending on the species whereas the Tbp1 proteintends to have a more consistent molecular weight with some variabilityacross the various bacteria which have TfR genes. The molecular weightof Tbp1 is usually in the range of 94 to 106,000 whereas the molecularweight of Tbp2 varies considerably from 58 to 98 000.

Amino acid sequencing of the N-termini and cyanogen bromide fragments oftransferrin receptor from H. influenzae DL63 was performed. TheN-terminus of Tbp2 was blocked but amino acid sequences were identifiedby sequencing of Tbp1 and are indicated by underlining within theprotein sequence of FIG. 3. These peptide sequences are Glu Thr Gln Serlle Lys Asp Thr Lys Glu Ala lle Ser Ser Glu Val Asp Tar (as shown inFIG. 3, SEQ ID NO: 101) and Leu Gln Leu Asn Leu Glu Lys Lys lle Gln GlnAsn Trp Leu Thr His Gln lle Ala Phe (as shown in FIG. 3; SEQ ID NO:102). The signal sequence of Tbp1 and the putative signal sequence ofTbp2 are indicated by double overligning in FIG. 3. The putative signalsequence for Tbp1 is Met Thr Lys Lys Pro Tyr Phe Arg Leu Ser Ile Ile SerCys Leu Leu Ile Ser Cys Tyr Val Lys Ala (SEQ ID NO: 103). The putativesignal sequence for Tbp2 is Met Lys Ser Val Pro Leu Ile Ser Gly Gly LeuSer Phe Leu Leu Ser Ala (SEQ ID NO: 104). The derived amino acidsequence of the N-terminal region of Tbp2 indicates that it is alipoprotein.

Chromosomal DNA from H. influenzae type b strain Eagan was prepared andlibraries were generated. The first library was constructed from DNApartially digested with Sau3A I, size-fractionated for ˜5-10 kbfragments, and cloned into a pUC-based plasmid. The second library wasconstructed from Eco RI- restricted chromosomal DNA fragments clonedinto λZAP. Both libraries were probed with a 5'-fragment of the pBHITclone as shown in FIG. 2 and partial clones of the TfR genes of H.influenzae Eagan termed S-4368-3-3 and JB-901-5-3 were obtained. Thus,referring to FIGS. 1B and 2, there is illustrated according to furtheraspects of the present invention, plasmid clones S-4368-3-3 andJB-901-5-3 encoding Tbp1 and Tbp2 from H. influenzae type b strainEagan. The DNA sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 2) fromH. influenzae type b strain Eagan and their deduced amino acid sequences(SEQ ID NOS: 7 and 8) are shown in FIG. 4 with the Tbp2 sequence beingthe first gene in the operon. In FIG. 4, putative -35, -10 and ribosomalbinding site sequences are overlined.

Chromosomal DNA from H. influenzae type b strain MinnA was prepared andthe DNA partially digested with Sau3A I, size-fractionated for 10-20 kbfragments, and cloned into the BamHI site of EMBL3. The library wasprobed with the 5'-fragment of the pBHIT clone (FIG. 2) and afull-length clone encoding TfR (DS-712-1-3) was obtained. Referring toFIGS. 1C and 2, there is illustrated according to additional aspects ofthe present invention, plasmid clone DS 712-1-3 encoding Tbp1 and Tbp2from H. influenzae type b strain MinnA. The DNA sequences of Tbp1 andTbp2 (SEQ ID NO: 3) and their deduced amino acid sequences (SEQ ID NO:9--Tbp1 and SEQ ID NO: 10--Tbp2) from H. influenzae type b strain MinnAare shown in FIG. 5 where the Tbp2 sequence is first in the operon. InFIG. 5, Putative -35, -10 and ribosomal binding site sequences areoverlined.

Chromosomal DNA from the non-typable H. influenzae strain PAK 12085 wasprepared. The DNA was partially digested with Sau3A I, size-fractionatedfor 10-20 kb fragments, and cloned into the BamH I site of EMBL3. Thelibrary was probed with the fragments of the pBHIT clone (FIG. 2) and afull-length clone encoding TfR (JB-1042-7-6) was obtained. Therestriction map of clone JB-1042-7-6 is shown in FIGS. 1D and 2 and thenucleotide sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 4) from H.influenzae PAK 12085 and their deduced amino acid sequences are shown inFIG. 6 (SEQ ID NOS: 11, 12), with the Tbp2 sequence first. In FIG. 6,Putative -35, -10 and ribosomal binding site sequences are overlined.

Chromosomal DNA from the otitis-media derived non-typable H. influenzaestrain SB33 was prepared. The DNA was partially digested with Sau3A I,size-fractionated for 10-20 kb fragments, and cloned into the BamH Isite of EMBL3. The library was probed with the fragments of the pBHITclone (FIG. 2) and a full-length clone encoding TfR (JB-1031-2-9) wasobtained. The restriction map of clone JB-1031-2-9 is shown in FIG. 2and the nucleotide sequences of the Tbp1 and Tbp2 genes (SEQ ID NO: 4)from H. influenzae SB33 and their deduced amino acid sequences are shownin FIG. 7 (SEQ ID NOS: 11, 12), with the Tbp2 sequence first. The SB33tbp2 gene was found to have a single base deletion which resulted in aframe-shift at residue 126 and premature truncation of the resultingprotein at residue 168.

PCR amplification of the tbp2 genes from otitis media-derived NTHistrains SB12, SB29, SB30 and SB32 was performed and the genes sequenced.

The nucleotide sequence of the tbp2 genes from non-typable H. influenzaestrains SB12 (SEQ ID NO: 105), SB29 (SEQ ID NO: 108), SB30 (SEQ ID NO:110) and SB32 (SEQ ID NO: 112) are shown in FIGS. 8, 9, 10 and 11respectively.

All of the amplified tbp2 genes were found to encode full-length Tbp2proteins indicating that the defective tbp2 gene of strain SB33 wasatypical.

The three H. influenzae b strains all had identical short intergenicsequences of only 13 bp between tbp2 and tbp1, but the NTHi strains PAK12085 and SB33 had longer intergenic sequences of 27 bp (FIG. 12).

Strain SB12 had a 13 bp intergenic sequence identical to that found inthe H. influenzae b strains while strains SB29, SB30 and SB32 containedlonger intergenic sequences (27-30 bp) as found in the other NTHistrains PAK 12085 and SB33 (FIG. 2B). All nine strains have a commoncore conserved 13 bp sequence between their tbp2 and tbp1 genes.

A pentapeptide sequence near the amino terminus of H. influenzae Tbp1was identified (FIG. 12) which is similar to the TonB box. The tonB geneof H. influenzae has been recently cloned and sequenced (Jarosik et al.,1994).

The amino acid sequences of Tbp1 from H. influenzae strains Eagan/MinnA,DL63, PAK12085 and SB33 strains are compared in FIG. 14. The Tbp1proteins of Eagan and MinnA are identical and 912 amino acids in length,that of DL63 has 914 residues, that of PAK 12085 has 914 residues, andthat of SB33 has 911 residues. The H. influenzae Tbp1 proteins arehighly conserved with 95-100% sequence identity. The amino acidsequences of Tbp2 from H. influenzae strains Eagan/MinnA, DL63, PAK12085 SB12, SB29, SB30 and SB32 are compared in FIG. 15. The Tbp2proteins of Eagan and MinnA are identical and contain 660 amino acids,that of DL63 has 644 residues, and that of PAK 12085 has 654 residues.There is a single base deletion in the SB33 tbp2 gene which results in aframe-shift at residue 126 and premature trunction of the resultingprotein at residue 168. The missing base was confirmed by directsequencing of PCR amplified chromosomal DNA. With the exception of Eaganand MinnA which are identical, the Tbp2 protein sequences are lessconserved with only 66-70% identity, but there are several shortsegments of conserved sequence which can be identified in FIG. 15. ThePCR amplified tbp2 genes from strains SB12, SB29, SB30 and SB32 were allfound to encode full-length Tbp2 proteins. There was sequence and sizeheterogeneity amongst the deduced Tbp2 proteins wherein SB12 had 648amino acids, SB29 had 631 residues, SB30 had 630 residues and SB32 had631 residues.

Putative secondary structures of Eagan Tbp1 and Tbp2 were determined(FIGS. 16A and 16B). Both proteins have several transmembrane domains,with Tbp1 traversing the membrane 20 times and Tbp2 crossing it 12times. Three exposed conserved epitopes were identified in the Tbp1amino-terminal region (DNEVTGLGK--SEQ ID NO: 43, EQVLN/DIRDLTRYD--SEQ IDNOS: 139 and 140, and GAINEIEYENVKAVEISK--SEQ ID NO: 141) and one in theC-terminal region (GI/VYNLF/LNYRYVTWE--SEQ ID NOS: 142 and 143). Onlythree small conserved regions can be identified within the Tbp2 proteinsof the human pathogens: CS/LGGG(G)SFD--SEQ ID NOS: 75, 144 and 145 atthe N-terminal, LE/SGGFY/FGP--SEQ ID NOS: 74 and 146 located internally,and VVFGAR/K--SEQ ID NOS: 83 and 84 at the C-terminus

The discovery that the Tbp2 amino acid sequence varies between strainsof Haemophilus allows for the grouping of Haemophilus into sub-groupsdefined by the same Tbp2 amino acid sequence. This discovery allows therational selection of a minimal number of Tbp1 and/or Tbp2 sequences orsynthetic peptides representing epitopes shared by such subtypes withinstrains of Haemophilus to be used in immunogenic compositions for, forexample, immunization against the diseases caused by Haemophilus andother bacteria that produce transferrin receptor with sequencesimilarities to Tbp1 and Tbp2 from Haemophilus species. Thus, a minimalnumber of transferrin receptor, analogs, fragments, and/or peptides, maybe used to immunize against many or all strains of Haemophilus and otherbacterial pathogens that produce transferrin receptor.

Furthermore, the amino acid sequences of the transferrin receptor from arange of bacterial pathogens (H. influenzae type b, non-typable H.influenzae, Neisseria meningitidis, Neisseria gonorrhoeae andActinobacillus (Haemophilus) pleuropneumoniae) were compared as shown inFIGS. 14 and 15. This analysis revealed regions of Tbp1 and Tbp2 whichare conserved between all of these bacteria. Some of such conservedsequences are contained in peptides in Tables 2 and 3. In particular thesequences DNEVTGLGK (SEQ ID: 43), EQVLNIRDLTRYDPGI (SEQ ID NO: 44),EQVLNIRDLTRYDPGISVVEQG RGASSGYSIRGMD (SEQ ID NO: 45),GAINEIEYENVKAVEISKG (SEQ ID NO: 46) and GALAGSV (SEQ ID NO: 47) areconserved in Tbp1 (Table 1 and FIG. 14). Particular conserved sequencesin Tbp2 include LEGGFYGP (SEQ ID NO: 74), CSGGGSFD (SEQ ID NO: 75),YVYSGL (SEQ ID NO: 76), CCSNLSYVKFG (SEQ ID NO: 77), FLLGERT (SEQ ID NO:78), EFNVOF (SEQ ID NO: 79), NAFTGTA (SEQ ID NO: 80), VNGAFYG (SEQ IDNO: 81), ELGGYF (SEQ ID NO: 82), VVFGAR (SEQ ID NO: 83) and VVFGAK (SEQID NO: 84) (Table 2 and FIG. 15).

The discovery of conserved sequences within the transferrin receptor ofa range of bacterial pathogens allows the selection of a minimal numberof antigens having particular amino acid sequences (including in theform of synthetic peptides) to immunize against the disease caused bypathogens that have transferrin receptors. Such bacteria in addition tothose recited above include other species of Neisseria, such asNeisseria gonorrhoeae, and Branhamella, including Branhamellacatarrhalis. Such conserved amino acid sequences among many bacterialpathogens permits the generation of TfR specific antibodies, includingmonoclonal antibodies, that recognize most if not all transferrinreceptors. Antiserum was raised against peptides corresponding toconserved portions of the transferrin receptor. This antiserumrecognized the transferrin receptor in Branhamella catarrhalis. Suchantisera are useful for the detection and neutralization of most if notall bacteria that produce TfR protein and are also useful for passiveimmunization against the diseases caused by such pathogens. Diagnosticassays and kits using such conserved amino acid sequences are useful todetect many if not all bacteria that produce transferrin receptor.

Epitopes containing the afore-mentioned amino acid sequences can bedelivered to cells of the immune system by the use of synthetic peptidescontaining such sequences, or by the use of live vectors expressing suchsequences, or by the direct administration of nucleic acid moleculesencoding the amino acid sequence.

Some peptides containing conserved amino acid sequences within the Tbp1proteins of H. influenzae type b strains Eagan, MinnA, DL63 and thenontypable strain PAK 12085 are shown in Table 2. Antibodies to some ofthese peptides were raised in guinea pigs (Table 4). Peptides containingconserved amino acid sequences within the Tbp2 proteins of H. influenzaetype b strains Eagan, Minn A, DL63 and the nontypable strain PAK 12085are shown in Table 3. Antibodies to some of these peptides were raisedin guinea pigs (Table 4).

The coding sequences of the Tbp1 and Tbp2 genes may be cloned intoappropriate expression vectors to produce recombinant proteins.Recombinant Tbp1 and Tbp2 were expressed from E. coli using the T7expression system. The tbp1 gene encoding the mature Eagan Tbp1 proteinwas cloned in-frame behind the T7 promoter generating plasmidJB-1468-29, as shown in FIG. 17. When introduced into BL21/DE3 cells andinduced with IPTG or lactose, Eagan Tbp1 protein was expressed as shownin FIG. 22.

The tbp2 gene encoding the mature Tbp2 protein was cloned in-framebehind the T7 promotor generating plasmid JB-1424-2-8 as shown in FIG.18. When introduced into E. coli cells and induced as above, Tbp2protein was expressed as shown in FIG. 22.

The tbp2 gene from strain NTHi SB12 was amplified by PCR. The resultantamplified DNA contains the authentic H. influenzae Tbp2 signal sequencebefore the mature protein. The SB12 tbp2 gene encoding the signalsequence and the mature protein was cloned into the pT7-7 expressionsystem as shown in FIG. 21. When the resultant plasmid (JB-1600-1) wasintroduced into E. coli BL21/DE3 cells and induced, SB12 Tbp2 wasexpressed, as shown in FIG. 22.

Recombinant proteins Tbp1 and Tbp2 produced in E. coli as inclusionbodies were purified by the scheme shown in FIG. 23. The purifiedproteins were at least about 70% pure as shown in FIG. 24.Immunogenicity studies were performed in mice with the purifiedrecombinant Tbp1 and Tbp2 proteins. Both proteins elicited a good immuneresponse in mice at 3-10 μg doses (FIG. 25).

Antisera raised to recombinant Tbp1 or Tbp2 derived from one H.influenzae strain are cross-reactive with other strains, making thesepotentially useful diagnostic reagents (FIGS. 26 and 27).

Plasmids pUHIT1KFH and pUHITKFP shown in FIG. 28, contain a selectableantibiotic resistance marker cloned within the transferrin receptoroperon and were constructed to insertionally inactivate the transferrinreceptor operon. These plasmids were used to transform Haemophilus togenerate strains that do not produce transferrin receptor Tbp1 and/orTbp2 as described in Example 19. Such strains are useful as negativecontrols (since they do not produce TfR) in in vitro and in vivodetection and diagnostic embodiments. Such strains are also expected tobe attenuated for in vivo growth and are useful as live vaccines toprovide protection against diseases caused by Haemophilus.

As discussed above, epitopes of transferrin receptor proteins can bedelivered to cells of the immune system by the use of live vectorsexpressing such amino acid sequences and the live vector may bepoliovirus. Referring to FIG. 29 there is illustrated the constructionof hybrid polioviruses expressing an epitope of transferrin receptorprotein including the conserved epitope from Tbp2 LEGGFYGP (SEQ ID NO:74). Such viruses were recognized by antibodies raised against a peptideincorporating the amino acid sequence LEGGFYGP (SEQ ID NO: 74) (Table 5)indicating that the viruses expressed this sequence in an antigenicallyrecognisable form. PV1TBP2A and PV1TBP2B were also neutralized by rabbitantisera raised against H. influenzae strain DL63 tbp2, indicating thatat least these two viruses expressed the sequence in a form recognisableto antibodies raised against the protein. All viruses were neutralisableby anti-PV1 sera, indicating that the changes in polio neutralizationantigenic site I had not significantly affected other antigenic sites onthe viruses. Furthermore, rabbit antiserum produced by immunization withpoliovirus chimera PV1TBP2A or PV1TBP2B recognized a peptideincorporating the amino acid sequence LEGGFYGP (SEQ ID NO: 74). Thisindicates that the sequences expressed by PV1TB2A and PV1TBP2B areimmunogenic and elicit antibodies capable of recognizing the samesequence in the context of a synthetic peptide.

Referring to FIG. 30, panel A shows an SDS PAGE gel showing purifiedrecombinant tbp2 from H. influenzae strain SB12 expressed in E. coli(lane 1), tbp2 from Branhamella catarrhalis strain 4223 (lane 2), awhole cell lysate of iron-limited B. catarrhalis strain 4223 (land 3), awhole cell lysate of iron-limited E. coli JM109 (lane 4), and a wholecell lysate of E. coli JM109 grown under non-iron limited conditions(lane 5). Panel B shows results of a Western blot of a replicate gelusing a pool of sera from rabbits immunized with PV1TBP2A. There was astrong reaction with the purified transferrin-binding proteins in lanes1 and 2, and with a similar sized band in lane 3. There was nosignificant reaction with any E. coli proteins (lanes 4 and 5). Panel Cshows the results for a pool of prebleed sera from the same rabbits,which displayed minimal specific reactivity. These results show thatPV1TBP2A is able to induce antisera specific for transferrin bindingproteins from H. influenzae and B. catarrhalis, and that the antiseracan distinguish B. catarrhalis from E. coli, which does not express anequivalent protein.

The purified and isolated DNA molecules comprising at least a portioncoding for a transferrin receptor of a species of Haemophilus typifiedby the embodiments described herein are advantageous as:

nucleic acid probes for the specific identification of Haemophilusstrains in vitro or in vivo.

the products encoded by the DNA molecules are useful as diagnosticreagents, antigens for the production of Haemophilus-specific antisera,for vaccination against the diseases caused by species of Haemophilusand (for example) detecting infection by Haemophilus.

peptides corresponding to portions of the transferrin receptor astypified by the embodiments described herein are advantageous asdiagnostic reagents, antigens for the production of Haemophilus-specificantisera, for vaccination against the diseases caused by species ofHaemophilus and (for example) for detecting infection by Haemophilus.

The transferrin receptor encoded by the nucleic acid molecules of thepresent invention, fragments and analogs thereof, and peptidescontaining sequences corresponding to portions of the transferrinreceptor that are conserved between various isolates of Haemophilus andother bacteria that produce transferrin receptor, are useful indiagnosis of and immunization against diseases caused by any bacterialstrain that produces transferrin receptor. In particular, peptidescontaining the sequences LEGGFYGP are conserved in the transferrinreceptor proteins of many bacterial pathogens that produce transferrinreceptor and are appropriate for diagnosis of and immunization againstdiseases caused by bacteria that produce transferrin receptor. Suchbacteria include but are not limited to species of Haemophilus,Neisseria (including N. meningitidis and N. gonorrhoeae) and Branhamella(including B. catarrhalis).

It is clearly apparent to one skilled in the art, that the variousembodiments of the present invention have many applications in thefields of vaccination, diagnosis, treatment of, for example, Haemophilusinfections, and infections with other bacterial pathogens that producetransferrin receptor and the generation of immunological reagents. Afurther non-limiting discussion of such uses is further presented below.

1. Vaccine Preparation and Use

Immunogenic compositions, suitable to be used as vaccines, may beprepared from immunogenic transferrin receptor, analogs and fragmentsthereof and/or peptides as disclosed herein. The vaccine elicits animmune response which produces antibodies, including anti-transferrinreceptor antibodies and antibodies that are opsonizing or bactericidal.Should the vaccinated subject be challenged by Haemophilus or otherbacteria that produce a transferrin receptor, the antibodies bind to thetransferrin receptor and thereby prevent access of the bacteria to aniron source which is required for viability. Furthermore, opsonizing orbactericidal anti-TfR antibodies may also provide protection byalternative mechanisms.

Vaccines containing peptides are generally well known in the art, asexemplified by U.S. Pat. Nos. 4,601,903; 4,599,231; 4,599,230; and4,596,792; all of which references are incorporated herein by reference.Immunogenic compositions including vaccines may be prepared asinjectables, as liquid solutions or emulsions. The transferrin receptor,analogs and fragments thereof and/or peptides may be mixed withpharmaceutically acceptable excipients which are compatible with thetransferrin receptor, fragments analogs or peptides. Such excipients mayinclude, water, saline, dextrose, glycerol, ethanol, and combinationsthereof. The immunogenic compositions and vaccines may further containauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, or adjuvants to enhance the effectiveness of the vaccines.Immunogenic compositions and vaccines may be administered parenterally,by injection subcutaneously or intramuscularly. Alternatively, theimmunogenic compositions formed according to the present invention, maybe formulated and delivered in a manner to evoke an immune response atmucosal surfaces. Thus, the immunogenic composition may be administeredto mucosal surfaces by, for example, the nasal or oral (intragastric)routes. The immunogenic composition may be provided in combination witha targeting molecule for delivery to specific cells of the immune systemor to mucosal surfaces. Some such targeting molecules include strain B12and fragments of bacterial toxins, as described in WO 92/17167 (BiotechAustralia Pty. Ltd.), and monoclonal antibodies, as described in U.S.Pat. No. 5,194,254 (Barber et al). Alternatively, other modes ofadministration including suppositories and oral formulations may bedesirable. For suppositories, binders and carriers may include, forexample, polyalkalene glycols or triglycerides. Oral formulations mayinclude normally employed incipients such as, for example,pharmaceutical grades of saccharine, cellulose and magnesium carbonate.These compositions take the form of solutions, suspensions, tablets,pills, capsules, sustained release formulations or powders and contain10-95% of the transferrin receptor, fragment analogs and/or peptides.

The vaccines are administered in a manner compatible with the dosageformulation, and in such amount as will be therapeutically effective,protective and immunogenic. The quantity to be administered depends onthe subject to be treated, including, for example, the capacity of theindividual's immune system to synthesize antibodies, and if needed, toproduce a cell-mediated immune response. Precise amounts of activeingredient required to be administered depend on the judgment of thepractitioner. However, suitable dosage ranges are readily determinableby one skilled in the art and may be of the order of micrograms of thetransferrin receptor, analogs and fragments thereof and/or peptides.Suitable regimes for initial administration and booster doses are alsovariable, but may include an initial administration followed bysubsequent administrations. The dosage of the vaccine may also depend onthe route of administration and will vary according to the size of thehost.

The nucleic acid molecules encoding the transferrin receptor of thepresent invention may also be used directly for immunization byadministration of the DNA directly, for example by injection for geneticimmunization or by constructing a live vector such as Salmonella, BCG,adenovirus, poxvirus, vaccinia or poliovirus. A discussion of some livevectors that have been used to carry heterologous antigens to the immunesystem are discussed in for example O'Hagan (1992). Processes for thedirect injection of DNA into test subjects for genetic immunization aredescribed in, for example, Ulmer et al., 1993.

The use of peptides in vivo may first require their chemicalmodification since the peptides themselves may not have a sufficientlylong serum and/or tissue half-life and/or sufficient immunogenicity.Such chemically modified peptides are referred to herein as "peptideanalogs". The term "peptide analog" extends to any functional chemicalequivalent of a peptide characterized by its increased stability and/orefficacy and immunogenicity in vivo or in vitro in respect of thepractice of the invention. The term "peptide analog" is also used hereinto extend to any amino acid derivative of the peptides as describedherein. Peptide analogs contemplated herein are produced by proceduresthat include, but are not limited to, modifications to side chains,incorporation of unnatural amino acids and/or their derivatives duringpeptide synthesis and the use of cross-linkers and other methods whichimpose conformational constraint on the peptides or their analogs.

Examples of side chain modifications contemplated by the presentinvention include modification of amino groups such as by reductivealkylation by reaction with an aldehyde followed by reduction with NaBH₄; amidation with methylacetimidate; acetylation with acetic anhydride;carbamylation of amino groups with cyanate; trinitrobenzylation of aminogroups with 2, 4, 6, trinitrobenzene sulfonic acid (TNBS); alkylation ofamino groups with succinic anhydride and tetrahydrophthalic anhydride;and pyridoxylation of lysine with pyridoxal-5'-phosphate followed byreduction with NaBH₄.

The guanidino group of arginine residues may be modified by theformation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal.

The carboxyl group may be modified by carbodiimide activation viao-acylisourea formation followed by subsequent derivatisation, forexample, to a corresponding amide.

Sulfhydryl groups may be modified by methods such as carboxymethylationwith iodoacetic acid or iodoacetamide; performic acid oxidation tocysteic acid; formation of mixed disulphides with other thiol compounds;reaction with maleimide; maleic anhydride or other substitutedmaleimide; formation of mercurial derivatives using4-chloromercuribenzoate, 4-chloromercuriphenylsulfonic acid,phenylmercury chloride, 2-chloromercuric-4-nitrophenol and othermercurials; carbamylation with cyanate at alkaline pH.

Tryptophan residues may be modified by, for example, oxidation withN-bromosuccinimide or alkylation of the indole ring with2-hydroxy-5-nitrobenzyl bromide or sulphonyl halides. Tryosine residuesmay be altered by nitration with tetranitromethane to form a3-nitrotyrosine derivative.

Modification of the imidazole ring of a histidine residue may beaccomplished by alkylation with iodoacetic acid derivatives orN-carbethoxylation with diethylpyrocarbonate.

Examples of incorporating unnatural amino acids and derivatives duringpeptide synthesis include, but are not limited to, use of norleucine,4-amino butyric acid, 4-amino-3-hydroxy-5-phenylpentanoic acid,6-aminohexanoic acid-, t-butylglycine, norvaline, phenylglycine,ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid,2-thienyl alanine and/or D-isomers of amino acids.

Immunogenicity can be significantly improved if the antigens areco-administered with adjuvants, commonly used as an 0.05 to 1.0 percentsolution in phosphate-buffered saline. Adjuvants enhance theimmunogenicity of an antigen but are not necessarily immunogenicthemselves. Adjuvants may act by retaining the antigen locally near thesite of administration to produce a depot effect facilitating a slow,sustained release of antigen to cells of the immune system. Adjuvantscan also attract cells of the immune system to an antigen depot andstimulate such cells to elicit immune responses.

Immunostimulatory agents or adjuvants have been used for many years toimprove the host immune responses to, for example, vaccines. Intrinsicadjuvants, such as lipopolysaccharides, normally are the components ofthe killed or attenuated bacteria used as vaccines. Extrinsic adjuvantsare immunomodulators which are typically non-covalently linked toantigens and are formulated to enhance the host immune responses. Thus,adjuvants have been identified that enhance the immune response toantigens delivered parenterally. Some of these adjuvants are toxic,however, and can cause undesirable side-effects, making them unsuitablefor use in humans and many animals. Indeed, only aluminum hydroxide andaluminim phosphate (collectively commonly referred to as alum) areroutinely used as adjuvants in human and veterinary vaccines. Theefficacy of alum in increasing antibody responses to diptheria andtetanus toxoids is will established and, more recently, a HBsAg vaccinehas been adjuvanted with alum. While the usefulness of alum is wellestablished for some applications, it has limitations. For example, alumis ineffective for influenza vaccination and inconsistently elicits acell mediated immune response. The antibodies elicited byalum-adjuvanted antigens are mainly of the IgG1 isotype in the mouse,which may not be optimal for protection by some vaccinal agents.

A wide range of extrinsic adjuvants can provoke potent immune responsesto antigens. These include saponins complexed to membrane proteinantigens (immune stimulating complexes), pluronic polymers with mineraloil, killed mycobacteria and mineral oil, Freund's complete adjuvant,bacterial products, such as muramyl dipeptide (MDP) andlipopolysaccharide (LPS), as well as lipid A, and liposomes.

To efficiently induce humoral immune responses (HIR) and cell-mediatedimmunity (CMI), immunogens are emulsified in adjuvants. Many adjuvantsare toxic, inducing granulomas, acute and chronic inflammations(Freund's complete adjuvant, FCA), cytolysis (saponins and pluronicpolymers) and pyrogenicity, arthritis and anterior uveitis (LPS andMDP). Although FCA is an excellent adjuvant and widely used in research,it is not licensed for use in human or veterinary vaccines because ofits toxicity.

Desirable characteristics of ideal adjuvants include:

(1) lack of toxicity;

(2) ability to stimulate a long-lasting immune response;

(3) simplicity of manufacture and stability in long-term storage;

(4) ability to elicit both CMI and HIR to antigens administered byvarious routes, if required;

(5) synergy with other adjuvants;

(6) capability of selectively interacting with populations of antigenpresenting cells (APC);

(7) ability to specifically elicit appropriate T_(H) 1 or T_(H) 2cell-specific immune responses; and

(8) ability to selectively increase appropriate antibody isotype levels(for example, IgA) against antigens.

U.S. Pat. No. 4,855,283 granted to Lockhoff et al on Aug. 8, 1989 whichis incorporated herein by reference thereto teaches glycolipid analoguesincluding N-glycosylamides, N-glycosylureas and N-glycosylcarbamates,each of which is substituted in the sugar residue by an amino acid, asimmuno-modulators or adjuvants. Thus, Lockhoff et al. 1991 reported thatN-glycolipid analogs displaying structural similarities to thenaturally-occurring glycolipids, such as glycosphingolipids andglycoglycerolipids, are capable of eliciting strong immune responses inboth herpes simplex virus vaccine and pseudorabies virus vaccine. Someglycolipids have been synthesized from long chain-alkylamines and fattyacids that are linked directly with the sugars through the anomericcarbon atom, to mimic the functions of the naturally occurring lipidresidues.

U.S. Pat. No. 4,258,029 granted to Moloney, assigned to the assigneehereof and incorporated herein by reference thereto, teaches thatoctadecyl tyrosine hydrochloride (OTH) functions as an adjuvant whencomplexed with tetanus toxoid and formalin inactivated type I, II andIII poliomyelitis virus vaccine. Also, Nixon-George et al. 1990,reported that octadecyl esters of aromatic amino acids complexed with arecombinant hepatitis B surface antigen, enhanced the host immuneresponses against hepatitis B virus.

Lipidation of synthetic peptides has also been used to increase theirimmunogenicity. Thus, Wiesmuller 1989, describes a peptide with asequence homologous to a foot-and-mouth disease viral protein coupled toan adjuvant tripalmityl-s-glyceryl-cysteinylserylserine, being asynthetic analogue of the N-terminal part of the lipoprotein from Gramnegative bacteria. Furthermore, Deres et al. 1989, reported in vivopriming of virus-lpecific cytotoxic T lymphocytes with syntheticlipopeptide vaccine which comprised of modified synthetic peptidesderived from influenza virus nucleoprotein by linkage to a lipopeptide,N-palmityl-s- 2,3-bis(palmitylxy)-(2RS)-propyl- R!-cysteine (TPC).

2. Immunoassays

The transferrin receptor, analogs and fragments thereof and/or peptidesof the present invention are useful as immunogens, as antigens inimmunoassays including enzyme-linked immunosorbent assays (ELISA), RIAsand other non-enzyme linked antibody binding assays or procedures knownin the art for the detection of antibacterial, Haemophilus, TfR and/orpeptide antibodies. In ELISA assays, the transferrin receptor, analogs,fragments and/or peptides corresponding to portions of TfR protein areimmobilized onto a selected surface, for example a surface capable ofbinding proteins or peptides such as the wells of a polystyrenemicrotiter plate. After washing to remove incompletely adsorbedtransferrin receptor, analogs, fragments and/or peptides, a nonspecificprotein such as a solution of bovine serum albumin (BSA) or casein thatis known to be antigenically neutral with regard to the test sample maybe bound to the selected surface. This allows for blocking ofnonspecific adsorption sites on the immobilizing surface and thusreduces the background caused by nonspecific bindings of antisera ontothe surface. Preferably, the selected peptides are from the conservedregions of Table 2 or Table 3 to enhance the cross-species detectionunless one particular bacterial species is to be detected. In thatevent, a polypeptide is selected which is unique to the TfR of thatparticular species. Normally, the peptides are in the range of 12residues and up and preferably 14 to 30 residues. It is understoodhowever, that a mixture of peptides may be used either as an immunogenin a vaccine or as a diagnostic agent. There may be circumstances wherea mixture of peptides from the conserved regions and/or from thenon-conserved regions are used to provide cross-species protectionand/or diagnosis. In this instance, the mixture of peptide immunogens iscommonly referred to as a "cocktail" preparation for use as a vaccine ordiagnostic agent.

The immobilizing surface is then contacted with a sample such asclinical or biological materials to be tested in a manner conducive toimmune complex (antigen/antibody) formation. This may include dilutingthe sample with diluents such as BSA, bovine gamma globulin (BGG) and/orphosphate buffered saline (PBS)/Tween. The sample is then allowed toincubate for from 2 to 4 hours, at temperatures such as of the order of25° to 37° C. Following incubation, the sample-contacted surface iswashed to remove non-immunocomplexed material. The washing procedure mayinclude washing with a solution such as PBS/Tween, or a borate buffer.

Following formation of specific immunocomplexes between the test sampleand the bound transferrin receptor, analogs, fragments and/or peptides,and subsequent washing, the occurrence, and even amount, ofimmunocomplex formation may be determined by subjecting theimmunocomplex to a second antibody having specificity for the firstantibody. If the test sample is of human origin, the second antibody isan antibody having specificity for human immunoglobulins and in generalIgG. To provide detecting means, the second antibody may have anassociated activity such as an enzymatic activity that will generate,for example, a color development upon incubating with an appropriatechromogenic substrate. Quantification may then achieved by measuring thedegree of color generation using, for example, a visible spectraspectrophotometer.

3. Use of Sequences as Hybridization Probes

The nucleotide sequences of the present invention, comprising thesequence of the transferrin receptor gene, now allow for theidentification and cloning of the transferrin receptor genes from anyspecies of Haemophilus and other bacteria that have transferrin receptorgenes.

The nucleotide sequences comprising the sequence of the transferrinreceptor genes of the present invention are useful for their ability toselectively form duplex molecules with complementary stretches of otherTfR genes. Depending on the application, a variety of hybridizationconditions may be employed to achieve varying degrees of selectivity ofthe probe toward the other TfR genes. For a high degree of selectivity,relatively stringent conditions are used to form the duplexes, such aslow salt and/or high temperature conditions, such as provided by 0.02Mto 0.15M NaCl at temperatures of between about 50° C. to 70° C. For someapplications, less stringent hybridization conditions are required suchas 0.15M to 0.9M salt, at temperatures ranging from between about 20° C.to 55° C. Hybridization conditions can also be rendered more stringentby the addition of increasing amounts of formamide, to destabilize thehybrid duplex. Thus, particular hybridization conditions can be readilymanipulated, and will generally be a method of choice depending on thedesired results. In general, convenient hybridization temperatures inthe presence of 50% formamide are: 42° C. for a probe which is 95 to100% homologous to the target fragment, 37° C. for 90 to 95% homologyand 32° C. for 85 to 90% homology.

In a clinical diagnostic embodiment, the nucleic acid sequences of theTfR genes of the present invention may be used in combination with anappropriate means, such as a label, for determining hybridization. Awide variety of appropriate indicator means are known in the art,including radioactive, enzymatic or other ligands, such asavidin/biotin, which are capable of providing a detectable signal. Insome diagnostic embodiments, an enzyme tag such as urease, alkalinephosphatase or peroxidase, instead of a radioactive tag may be used. Inthe case of enzyme tags, colorimetric indicator substrates are knownwhich can be employed to provide a means visible to the human eye orspectrophotometrically, to identify specific hybridization with samplescontaining TfR gene sequences.

The nucleic acid sequences of TfR genes of the present invention areuseful as hybridization probes in solution hybridizations and inembodiments employing solid-phase procedures. In embodiments involvingsolid-phase procedures, the test DNA (or RNA) from samples, such asclinical samples, including exudates, body fluids (e.g., serum, amnioticfluid, middle ear effusion, sputum, bronchoalveolar lavage fluid) oreven tissues, is adsorbed or otherwise affixed to a selected matrix orsurface. The fixed, single-stranded nucleic acid is then subjected tospecific hybridization with selected probes comprising the nucleic acidsequences of the TfR genes or fragments thereof of the present inventionunder desired conditions. The selected conditions will depend on theparticular circumstances based on the particular criteria requireddepending on, for example, the G+C contents, type of target nucleicacid, source of nucleic acid, size of hybridization probe etc. Followingwashing of the hybridization surface so as to remove non-specificallybound probe molecules, specific hybridization is detected, or evenquantified, by means of the label. As with the selection of peptides, itis preferred to select nucleic acid sequence portions which areconserved among species of Haemophilus, such as nucleic acid sequencesencoding the conserved peptide sequence of FIGS. 8, 9, 13 and 14 andparticularly listed in Tables 2 and 3. The selected probe may be atleast 18 bp and may be in the range of 30 bp to 90 bp long.

4. Expression of the Transferrin Receptor Genes

Plasmid vectors containing replicon and control sequences which arederived from species compatible with the host cell may be used for theexpression of the transferrin receptor genes in expression systems. Thevector ordinarily carries a replication site, as well as markingsequences which are capable of providing phenotypic selection intransformed cells. For example, E. coli may be transformed using pBR322which contains genes for ampicillin and tetracycline resistance and thusprovides easy means for identifying transformed cells. The pBR322plasmid, or other microbial plasmid or phage must also contain, or bemodified to contain, promoters which can be used by the host cell forexpression of its own proteins.

In addition, phage vectors containing replicon and control sequencesthat are compatible with the host can be used as a transforming vectorin connection with these hosts. For example, the phage in lambda GEM™-11may be utilized in making recombinant phage vectors which can be used totransform host cells, such as E. coli LE392.

Promoters commonly used in recombinant DNA construction include theβ-lactamase (penicillinase) and lactose promoter systems (Chang et al.,1978: Itakura et al., 1977 Goeddel et al., 1979; Goeddel et al., 1980)and other microbial promoters such as the T7 promoter system (U.S. Pat.No. 4,952,496). Details concerning the nucleotide sequences of promotersare known, enabling a skilled worker to ligate them functionally withgenes. The particular promoter used will generally be a matter of choicedepending upon the desired results. Hosts that are appropriate forexpression of the transferrin receptor genes, fragment analogs orvariants thereof include E. coli, Bacillus species, Haemophilus, fungi,yeast or the baculovirus expression system may be used.

In accordance with this invention, it is preferred to make the proteinby recombinant methods, particularly when the naturally occurring TfRprotein as purified from a culture of a species of Haemophilus mayinclude trace amounts of toxic materials or other contaminants Thisproblem can be avoided by using recombinantly produced TfR protein inheterologous systems which can be isolated from the host in a manner tominimize comtaminants in the purified material. Particularly desirablehosts for expression in this regard include Gram positive bacteria whichdo not have LPS and are therefore endotoxin free. Such hosts includespecies of Bacillus and may be particularly useful for the production ofnon-pyrogenic transferrin receptor, fragments or analogs thereof.Furthermore, recombinant methods of production permit the manufacture ofTbp1 or Tbp2 or fragments thereof separate from one another which isdistinct from the normal combined proteins present in Haemophilus.

Biological Deposits

Certain plasmids that contain at least a portion coding for atransferrin receptor from strains of Haemophilus influenzae that aredescribed and referred to herein have been deposited with the AmericanType Culture Collection (ATCC) located at Rockville, Md. U.S.A. pursuantto the Budapest Treaty and prior to the filing of this application.Samples of the deposited plasmids will become available to the publicupon grant of a patent based upon this United States patent application.The invention described and claimed herein is not to be limited in scopeby plasmids deposited, since the deposited embodiment is intended onlyas an illustration of the invention. Any equivalent or similar plasmidsthat encode similar or equivalent antigens as described in thisapplication are within the scope of the invention.

Deposit Summary

    ______________________________________                                                  ATCC                                                                Clone     Designation    Date Deposited                                       ______________________________________                                        DS-712-1-3                                                                              75603          November 4, 1993                                     JB-1042-7-6                                                                             75607          November 4, 1993                                     JB-1424-2-8                                                                             75937          October 27, 1994                                     JB-1600-1 75935          October 27, 1994                                     JB-1468-29                                                                              75936          October 27, 1994                                     pT7TBP2A  75931          October 27, 1994                                     pT7TBP2B  75932          October 27, 1994                                     pT7TBP2C  75933          October 27, 1994                                     pT7TBP2D  75934          October 27, 1994                                     ______________________________________                                    

Strains of Haemophilus

Hib strain Eagan is available from Connaught Laboratories Limited, 1755Steeles Ave. W., Willowdale, Ontario, Canada M2R 3T4.

Hib strain MinnA was obtained from the collection of Dr. Robert Munson,Department of Microbiology and Immunology, Washington University Schoolof Medicine, Children's Hospital, St. Louis, Mo. 63110.

Hib strain DL63 was obtained from the collection of Dr. Eric Hansen,Department of Microbiology, University of Texas Southwestern MedicalCenter, 5323 Harry Hines Boulevard, Dallas, Tex. 75235-9048.

PAK 12085 was obtained from the collection of Dr. Robert Munson (supra).

SB12, 29, 30, 32 and 33 were obtained from the collection of Dr. StephenBarenkamp, Department of Pediatrics, School of Medicine, Saint LouisUniversity Medical Centre, St. Louis, Mo. 63104.

EXAMPLES

The above disclosure generally describes the present invention. A morecomplete understanding can be obtained by reference to the followingspecific Examples. These Examples are described solely for purposes ofillustration and are not intended to limit the scope of the invention.Changes in form and substitution of equivalents are contemplated ascircumstances may suggest or render expedient. Although specific termshave been employed herein, such terms are intended in a descriptivesense and not for purposes of limitations.

Methods of molecular genetics, protein biochemistry, immunology andfermentation technology used but not explicitly described in thisdisclosure and these Examples are amply reported in the scientificliterature and are well within the ability of those skilled in the art.

Example 1

This Example illustrates the preparation of chromosomal DNA from H.influenzae strains DL63, Eagan, MinnA, and PAK 12085, and SB33.

H. influenzae strains were grown on Mueller-Hinton agar or in brainheart infusion broth as described by Harkness et al 1992.

A. Chromosomal DNA Extraction from Haemophilus influenzae type b DL63

Chromosomal DNA was prepared as follows. Two hundred and fifty ml ofculture were pelleted by centrifugation at 8,000 rpm in a Beckman J14rotor for 15 minutes. The pellet was washed with 200 ml of 50 mMTris-HCl, pH 8.0, centrifuged as before, resuspended in 12.5 ml of 50 mMTris-HCl, 50 mM EDTA, pH 8.0, and frozen at -20° C. Then 1.25 ml of a 10mg/ml lysozyme solution in 0.25M Tris-HCl, pH 8.0, was added to thefrozen cell pellet. The pellet was thawed and incubated on ice for 45minutes. Next, 2.5 ml of a solution of 1 mg/ml proteinase K in 0.5% SDS,0.4M EDTA, 50 mM Tris-HCl, pH 7.5 was added and the mixture incubated at50° C. for 1 hour with occasional mixing. The lysate was extracted oncewith 15 ml of Tris-buffered phenol, then 1.5 ml of 3M sodium acetate and30 ml of ethanol were added to precipitate the DNA. The DNA was spooledon a glass rod, then dissolved in 12.5 ml of 50 mM Tris-HCl, 1 mM EDTA,pH 7.5 containing 0.2 mg/ml RNAse A by rocking overnight. The sample wasextracted once with an equal volume of chloroform, precipitated, andspooled as above. The DNA was dissolved in 2 ml of 50 mM Tris-HCl, 1 mMEDTA, pH 7.5 and stored at 4° C.

B. Chromosomal DNA Extraction from Haemophilus influenzae Type b Eagan

Fifty ml of culture were pelleted by centrifugation, the pelletresuspended in 25 ml of TE (10 mM Tris, 1 mM EDTA, pH 7.5), and 2×5 mlaliquots used for chromosomal DNA preparation. To each aliquot was added0.6 ml of 10% sarkosyl and 0.15 ml of 20 mg/ml proteinase K and thesamples incubated at 37° C. for 1 hour. The lysate was extracted oncewith Tris-saturated phenol and three times with chloroform:isoamylalcohol (24:1). The aqueous phases were pooled for a final volume of 7ml. Then 0.7 ml of 3M sodium acetate (pH 5.2) and 4.3 ml of isopropanolwere added to precipitate the DNA which was spooled, rinsed with 70%ethanol, dried, and resuspended in 1 ml of water.

C. Chromosomal DNA Extraction from Haemophilus influenzae Eagan, MinnA,PAK 12085 and SB33

Cells were pelleted from 50 ml of culture by centrifugation at 5000 rpmfor 15-20 minutes, at 4° C. The cell pellet was resuspended in 10 ml ofTE (10 mM Tris-HCl, 1 mM EDTA, pH 7.5), pronase and SDS were added tofinal concentrations of 500 μg/ml and 1%, respectively. The sample wasincubated at 37° C. for 4 hours until a clear lysate was obtained. Thelysate was extracted once with Tris-saturated phenol, once withTris-saturated phenol/chloroform (1:1), and once with chloroform. Thefinal aqueous phase was dialysed for 24 hours against 2×500 ml of 1MNaCl at 4° C., changing the buffer once, and for 24 hours against 2×500ml of TE at 4° C., changing the buffer once. The final dialysate wasaliquotted for use.

Example 2

This Example illustrates the preparation of chromosomal libraries.

A. H. influenzae DL63-λZAP Library

100 μg of H. influenzae DL63 chromosomal DNA in TE was mechanicallysheared in a I ml syringe with a 25 gauge needle. The sheared DNA wasmade blunt-ended by adding water to a final volume of 405 μl, 45 μl of10×S1 nuclease buffer (2M NaCl, 500 mM NaOAc, pH 4.5, 10 mM ZnSO₄, 5%glycerol), and 1.7 μl of S1 nuclease at 100 U/μl and incubating at 37°C. for 15 min. The sample was extracted once with phenol/chloroform andonce with chloroform and 1 ml of ethanol was added to precipitate theDNA. The sample was incubated on ice for 10 min or at -20° C. overnightand the DNA was harvested by centrifugation in a microfuge for 30minutes. The DNA was washed with 70% ethanol and dried. The Eco RI sitesin the DNA sequence were methylated using standard procedures. To thismethylated DNA was added 5 μl of 100 mM MgCl₂, 8 μl of dNTP mix (2.5 mMeach of dATP, dCTP, dGTP, and dTTP), and 4 μl of 5 U/μl Klenow. Themixture was incubated at 12° C. for 30 minutes. 450 μl of STE (0.1MNaCl, 10 mM Tris-HCl, 1 mM EDTA, pH 8.0) were added, and the mixtureextracted once with phenol/chloroform, and once with chloroform, beforeadding 1 ml of ethanol to precipitate the DNA. The sample was incubatedon ice for 10 min or at -20° C. overnight. The DNA was harvested bycentrifugation in a microfuge for 30 minutes, washed with 70% ethanoland dried.

The DNA was resuspended in 7 μl of TE and to the solution was added 14μl of phosphorylated Eco RI linkers (200 ng/μl), 3 μl of 10× ligationbuffer, 3 μl of 10 mM ATP, and 3 μl of T4 DNA ligase (4 U/μl). Thesample was incubated at 4° C. overnight, then incubated at 68° C. for 10minutes to inactivate the ligase. To the mixture was added 218 μl of H₂O, 45 μl of 10× Universal buffer, and 7 μl of Eco RI at 30 U/μl. Afterincubation at 37° C. for 1.5 hours, 1.5 μl of 0.5M EDTA was added, andthe mixture placed on ice.

The DNA was size fractionated on a sucrose gradient, pooling fractionscontaining DNA of 6-10 kb. The pooled DNA was ethanol precipitated andresuspended in 5 μl of TE buffer. 200 ng of insert DNA was ligated for2-3 days at 4° C. with 1 μg of ZAP II vector in a final volume of 5 μl.The ligation mixture was packaged using Gigapack II Gold (Stratagene)and plated on E. coli SURE cells on NZY plates. The library wastitrated, amplified, and stored at 4° C. under 0.3% chloroform.

B. H. influenzae Eagan-pUC Library

Chromosomal DNA prepared from H. influenzae Eagan by the method inExample 1C was digested with Sau3A I for 2, 5, and 10 minutes andsamples electrophoresed on a preparative agarose gel. Gel slices whichincluded DNA fragments between 3-10 kb in length were excised and theDNA extracted by the standard freeze-thaw procedure. Plasmid DNA frompUC 8:2 (pUC 8 with additional Bgl II and Xba I restriction enzyme sitesin the multiple cloning site) was digested with BamH I and Bgl II, anddephosphorylated with calf alkaline phosphatase (CAP). The fragments ofH. influenzae Eagan DNA were ligated into pUC and the mixture used totransform E. coli JM109 cells.

C. H. influenzae Eagan-λZAP library

Chromosomal DNA from H. influenzae Eagan prepared as in Example 1B wasdigested with Eco RI and size fractionated on a preparative agarose gel.Gel slices corresponding to DNA fragments of 7-23 kb were excised andDNA was electroeluted overnight in dialysis tubing containing 3 ml ofTAE (40 mM Tris-acetate, 1 mM EDTA) at 14V. The DNA was precipitatedtwice and resuspended in water before being ligated overnight with EcoRI digested λZAP II DNA. The ligation mixture was packaged using theGigapack II packaging kit (Stratagene) and plated on E. coli XL1-Bluecells. The library was titrated, amplified, and stored at 4° C. under0.3% chloroform.

D. EMBL3 Libraries

H. influenzae MinnA chromosomal DNA (10 μg) was prepared as in Example1C and digested with Sau3A I (40 units) for 2, 4, and 6 minutes thensize-fractionated on a 10-30% sucrose gradient in TNE buffer (20 mMTris-HCl, 5 mM NaCl, 1 mM EDTA, pH 8). Fractions containing DNAfragments greater than 5 kb were pooled and precipitated. In a secondexperiment, chromosomal DNA (2.6 μg) was digested with Sau3A I (4 units)for 1, 2, and 3 minutes and size-fractionated by preparative agarose gelelectrophoresis. Gel slices containing DNA fragments of 10-20 kb wereexcised and DNA extracted by a standard freeze/thaw technique. Thesize-fractionated DNA from the two experiments was pooled for ligationwith BamH I arms of EMBL3 (Promega). The ligation mixture was packagedusing the Gigapack II packaging kit and plated on E. coli LE392 cells.The library was titrated, then amplified and stored at 4° C. under 0.3%chloroform.

Chromosomal DNA from H. influenzae PAK12085 or SB33 prepared as inExample 1C was digested with Sau3A I (0.5 units/10 μg DNA) at 37° C. for15 minutes and size-fractionated by agarose gel electrophoresis. Gelslices corresponding to DNA fragments of 15-23 kb were excised and DNAwas electroeluted overnight in dialysis tubing containing 3 ml of TAE at14V. The DNA was precipitated twice and resuspended in water beforeovernight ligation with EMBL3 BamH I arms (Promega). The ligationmixture was packaged using the Lambda in vitro packaging kit (Amersham)according to the manufacturer's instructions and plated onto E. coliNM539 cells. The library was titrated, then amplified, and stored at 4°C. in the presence of 0.3% chloroform.

Example 3

This Example illustrates screening of the libraries

A. H. influenzae DL63-λZAP Expression Library

Tbp1 and Tbp2 proteins were affinity purified on solid phase humantransferrin (hTf). Briefly, a 20 ml hTf-Sepharose column was preparedaccording to the manufacturer's protocol for coupling protein ligands toCNBr-activated Sepharose (Sigma). The resulting matrix was washed with 3column volumes of 50 mM Tris-HCl, 1M NaCl, 6M guanidine-HCl, pH 8.0 toremove non-covalently bound hTf. The column was then equilibrated with50 mM Tris-HCl, pH 8.0 and bound hTf was iron loaded using 1 ml of 10mg/ml FeCl₃ in buffer containing 100 mM each of sodium citrate andsodium bicarbonate, pH 8.6, followed by 2 column volumes of 50 mMTris-HCl, 1M NaCl, pH 8.0. Total bacterial membranes (300 mg totalprotein) were prepared from H. influenzae strain DL63 grown on irondeficient media as described previously (Schryvers et al., 1989).Membranes were diluted to 2 mg/ml in 50 mM Tris-HCl, 1M NaCl, pH 8.0 andsolubilized by the addition of EDTA to 15 mM and Sarkosyl NL97 to 1.5%.After centrifugation at 40,000× g for 1 hour, the supernatant wasapplied to the hTf column and the column washed with 10 column volumesof 50 mM Tris-HCl, 1M NaCl, 10 mM EDTA, 0.5% Sarkosyl, pH 8.0. Thereceptor proteins were eluted using 2M GnHCl in the same buffer and theeluted fractions were dialysed extensively against 25 mM ammoniumbicarbonate buffer (5 buffer changes), lyophilized, and stored at -20°C. Isolated proteins were used to generate transferrin receptor-specificantisera in New Zealand White rabbits using standard techniques.Briefly, rabbits were immunized 3 times subcutaneously, at intervals oftwo weeks, using complete Freund's adjuvant for the first injection andincomplete Freund's adjuvant for subsequent injections.

The DL63 λZAP library was plated on E. coli SURE cells and plaques weretransferred onto nitrocellulose membranes which had been pre-soaked in10 mM IPTG to induce expression from the pBluescript lacZ promoter.Filters were blocked using 0.5% skim milk in 50 mM Tris-HCl, 150 mMNaCl, pH 7.5, prior to being probed with the polyclonal anti-TfRantisera and horse radish peroxidase-conjugated goat anti-rabbit IgG.Plaques were purified by 3 rounds of screening and recombinantpBluescript plasmids (pBHIT1 and pBHIT2; FIGS. 1A and 2) were recoveredby the in vivo excision procedure (Short et al., 1988).

B. Eagan, MinnA, and PAK12085 Non-Expression Libraries

(i) Screening of H. influenzae Eagan-pUC Library

Colony lifts onto nitrocellulose were performed using standardtechniques and the filters were probed with the 5'pBHIT2 probe of thetransferrin receptor gene illustrated in FIG. 2. The probe was labelledwith digoxigenin (dig, Boshringer Mannheim) following the manufacturer'sspecifications. Several putative clones were dot blotted ontonitrocellulose and submitted to second round screening using the same5'pBHIT2 probe. Second round putatives were analysed by restrictionenzyme mapping and clone S-4368-3-3 (FIG. 1B, FIG. 2) was selected forsequence analysis.

(ii) Screening H. influenzae Eagan-λZAP Library

The phage library was plated using standard techniques on XLI Blue cells(Stratagene) using LB plates and a 0.7% agarose overlay layer. Plaqueswere lifted onto nitrocellulose using standard protocols and the filterswere baked at 80° C., for 2 hours, under vacuum, to fix the DNA. The5'pBHIT2 probe of the transferrin receptor gene (FIG. 2) was labelledwith digoxigenin and the filters were pre-hybridized for 4 hours at 42°C., then hybridized with the labelled probe at 42° C., overnight. Thefilters were washed at 68° C. and after autoradiography, several plaqueswere selected for second round screening. In vivo excision of phagemidDNA from second round putatives was performed according to protocolsprovided with the λZAP system (Promega). Four clones with identical ˜2.5kb Eco RI inserts were obtained of which JB-901-5-3 in FIG. B, FIG. 2 isan example. Putative plaques were also amplified and phage DNA waspurified from 500 ml of culture. Insert DNA was excised by digestionwith Xba I and was cloned into pUC 8:2 (pUC 8 containing additional BglII and Xba I sites in its multiple cloning site) which had been digestedwith Xba I and dephosphorylated. Clone JB-911-3-2 (FIG. 17) contains the3'-half of the H. influenzae Eagan TfR operon.

(iii) Screening EMBL 3 Libraries

The H. influenzae MinnA library was plated onto LE392 cells on NZCYMplates using 0.7% top agarose in NZCYM as overlay. Plaque lifts ontonitrocellulose filters were performed following standard procedures, andfilters were processed and probed with the 5'pBHIT2 probe (FIG. 2)labelled with digoxigenin. Putative plaques were plated and submitted tosecond and third rounds of screening using the same procedures. PhageDNA was prepared from 500 ml of culture using standard techniques, theinsert DNA excised by Sal I digestion, and cloned into pUC to generateclone DS-712-1-3 (FIGS. 1C and 2).

The H. influenzae PAK 12085 library was plated on LE392 cells on NZCYMplates using 0.7% agarose in NZCYM as overlay. Plaques were lifted ontonitrocellulose and filters were processed and probed with thedigoxigenin-labelled 5'pBHIT2 probe (FIG. 2). Putative plaques wereplated and subjected to a second round of screening using the sameprocedures. Phage DNA was prepared from 500 ml cultures-by standardtechniques, the DNA insert was excised by digestion with Sal I, andcloned into pUC to generate clone JB-1042-7-6 (FIGS. 1D and 2).

The H. influenzae SB33 library was plated on LE392 cells on NZCYM platesusing 0.7% agarose in NZCYM as overlay. Plaques were lifted ontonitrocellulose and filters were processed and probed with thedigoxigenin-labelled 5'pBHIT2 probe (FIG. 2). Putative plaques wereplated and subjected to a second round of screening using the sameprocedures. Phage DNA was prepared from 500 ml cultures by standardtechniques, the DNA insert was excised by digestion with Sal I, andcloned into pUC to generate clone JB-1031-2-9 (FIG. 2).

Example 4

This Example illustrates the sequencing of the Tbp1 and Tbp2 genes ofthe TfR operon.

Plasmid DNA from clones pBHIT 1, pBHIT 2, S-4368-3-3, JB-901-5-3,DS-712-1-3, JB-1042-7-6 and JB-1031-2-9 was prepared using standardtechniques. Oligonucleotide sequencing primers of 17-25 bases in lengthwere synthesized on the ABI model 380B DNA Synthesizer and purified bychromatography using OPC cartridges obtained from Applied BiosystemsInc., and used in accordance with the manufactures recommendations.Samples were sequenced using the ABI model 370A DNA Sequencer and dyeterminator chemistry according to manufacturers' protocols. The sequenceof the TfR operon from strain DL63 is illustrated in FIG. 3, that ofstrain Eagan in FIG. 4, that of strain MinnA in FIG. 5, that of PAK12085 in FIG. 6 and that of SB33 in FIG. 7.

Example 5

This Example illustrates the PCR amplification of the tbp2 genes fromnon-typable H. influenzae strains SB12, SB29, SB30, and SB32.

Chromosomal DNA from non-typable H. influenzae strains SB12, SB29, SB30,and SB32 was prepared as described aobve. The TfR genes are arranged asan operon with tbp2 followed by tbp1 (see FIGS. 12A and 12E).Oligonucleotides were synthesized to the 5'-end of the tbp2 and thereverse complement of the 5'-end of the tbp1 coding sequences. Theprimers were: GGATCCATATGAAATCTGT ACCTCTTATCTCTGGT (SEQ ID NO: 120)corresponding to MKSVPLISGS (SEQ ID NO: 147) from the leader sequence ofTbp2 and TCTAGAAGCTTTTTTAGTCATTTTTAGTATTCCAT (SEQ ID NO: 137) which isthe reverse complement of the leader sequence MTKK (SEQ ID NO: 138) ofTbp1 and a part of the intergenic sequence (FIGS. 12A and 12B). PCRamplification was performed in buffer containing 10 mM Tris/HCl pH 8.3,50 mM potassium chloride and 1.5 mM magnesium chloride. Each 100 μlreaction mixture contained 5 ng of chromosomal DNA, 1 ∥g of each primer,5 units amplitaq DNA polymerase (Perkin Elmer Cetus) and 0.4 mM dNTPs(Perkin Elmer Cetus). The cycling conditions were 25 cycles of 94° C.for 1.0 min, 45° C. for 2.0 min and 72° C. for 1.5 min. Specific 2 kbfragments were amplified for each sample (FIG. 13). SB33 DNA was used asa positive control (Lane 1). Chromosomal DNA used for amplification ofthe Tbp2 gene were lane 1, SB33; lane 2, SB12; lane 3, SB29; lane 4,SB30; and lane 5, SB32. The fragments were cloned into the TA cloningvector (Invitrogen) and their nucleotide sequences determined. Thenucleic acid sequences of Tbp2 from strains SB12 (SEQ ID NO: 108), SB29(SEQ ID NO: 110), SB30 (SEQ ID NO: 112) and SB32 (SEQ ID NO: 114) areshown in FIGS. 8, 9 10 and 11 respectively.

Example 6

This Example illustrates the comparison of the amino acid sequences oftransferrin the identification of potentially exposed epitopes oftransferrin receptor proteins by secondary structure analysis.

Referring to FIG. 14, there is shown a comparison of the amino acidsequence of Tbp1 from H. influenzae type b Eagan, DL63, non-typable H.influenzae strains PAK 12085 and SB33, N. meningitidis strains B16B6 andM982 (Legrain et al., 1993) and N. gonorrhoeae FA19 (Cornelissen et al.,1992). This analysis revealed regions of Tbp1 which are conserved amongall these bacteria.

Referring to FIG. 15, there is shown a comparison of the amino acidsequence of Tbp2 from H. influenzae type b strains Eagan, DL63,non-typable H. influenzae PAK 12085, SB12, SB29, SB30 and SB32, N.meningitidis strains B16B6 and M982, N. gonorrhoeae FA19 andActinobacillus (Haemophilus) pleuropneumoniae (Gerlach et al., 1992) 205and 37. This analysis revealed regions of Tbp2 which are conserved amongall these bacteria.

Protein secondary structure analyses were performed using the Chou andFasman algorithms (1978) and hydrophilicity/hydrophobicity plots wereperformed using the Hopp algorithm (1986). The values were derived fromthe averages of heptapeptide windows and are plotted at the midpoint ofeach fragment. FIG. 16A illustrates the predicted secondary structure ofTbp1 from H. influenzae type b Eagan and FIG. 16B illustrates thepredicted secondary structure of Tbp2 from H. influenzae type b Eagan.The predicted secondary structures depicted in FIGS. 16A and 16B werearrived at using the procedures described above. However, the inventorshave not yet been able to verify that the secondary structure isaccurately depicted by these Figures.

Conserved epitopes of Tbp1 and Tbp2 proteins from several differentbacteria were identified by sequence alignment as shown in FIGS. 14 and15 respectively.

Some such conserved epitopes include:

    ______________________________________                                        TBP1     DNEVTGLGK          SEQ ID NO:43                                      TBP1     EQVLNIRLTRYDPGI    SEQ ID NO:44                                      TBP1     GAINEIEYENVKAVEISKG                                                                              SEQ ID NO:45                                      TBP1     GALAGSV            SEQ ID NO:46                                      TBP2     LEGGFYGP           SEQ ID NO:74                                      TBP2     CSGGGSFD           SEQ ID NO:75                                      TBP2     YVYSGL             SEQ ID NO:76                                      TBP2     CCSNLSYVKFG        SEQ ID NO:77                                      TBP2     FLLGHRT            SEQ ID NO:78                                      TBP2     EFNVDF             SEQ ID NO:79                                      TBP2     NAFTGTA            SEQ ID NO:80                                      TBP2     VNGAFYG            SEQ ID NO:81                                      TBP2     LEGGYF             SEQ ID NO:82                                      TBP2     VVFGAR             SEQ ID NO:83                                      ______________________________________                                    

Furthermore, in combination with the predicted secondary structures,four conserved exposed epitopes were identified on Tbp1 and two wereidentified on Tbp2.

These are:

    ______________________________________                                        Tbp1  DNEVTGLGK        SEQ ID NO:43                                           Tbp1  EQVLN/DIRDLTRYD  SEQ ID NOS:139 and 140                                 Tbp1  GAINEIEYENVKAVEISK                                                                             SEQ ID NO:141                                          Tbp1  GI/VYNLF/LNYRYVTWE                                                                             SEQ ID NOS:142 and 143                                 Tbp2  CS/LGGG(G)SFD    SEQ ID NOS:75, 144 and 145                             Tbp2  LE/SGGFY/FGP     SEQ ID NOS:74 and 146                                  ______________________________________                                    

Proteins, polypeptides or peptides containing the afore-mentionedconserved amino acid sequences are particularly useful as detectingmeans in diagnostic embodiments and as immunogens to detect or protectfrom diseases caused by bacteria that produce transferrin receptorprotein. For immunization, the particularly indicated amino acidsequences may be presented to the immune system as proteins or peptidesor a live delivery vehicle, such as Salmonella, BCG, adenovirus,poxvirus, vaccinia or poliovirus may be used.

Example 7

This Example illustrates the construction of plasmid JB-1468-29 whichexpresses Eagan Tbp1 from E. coli.

Plasmids S-4368-3-3 (FIGS. 1B and 2) and JB-911-3-2 (FIG. 17) containthe 5'- and 3'-parts of the Eagan tbp1 gene, respectively. FIG. 17illustrates the construction scheme for plasmid JB-1468-29. Theoligonucleotide sequences used in the construction of JB-1468-29 areshown in FIG. 20, (SEQ ID NOS: 86 and 87). Plasmid JB-1468-29 wasintroduced into E. coli strain BL21/DE3 by electroporation to generatestrain JB-1476-2-1.

JB-1476-2-1 was grown in YT medium and induced with IPTG followingstandard protocols. For preparation of Tbp1 for immunogenicity and otherstudies, strain JB-1476-2-1 was grown overnight in NZCYM mediacontaining 3% glucose. A 1:40 inoculum was added to fresh NZCYM mediawithout glucose, and the culture grown to A₅₇₈ =0.3. Lactose was addedto 1% and the culture was induced for 4 hours. SDS-PAGE analysis ofwhole cell lysates of JB-1476-2-1 is shown in FIG. 22. Lane 1,JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4 hinduction; lane 3, molecular weight markers of 200 kDa, 116 kDa, 97.4kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) att_(o) ; lane 5, JB-1437-4-1 at t=4 h induction; lane 6, JB-1607-1-1(T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4 h induction.

Example 8

This Example illustrates the construction of plasmid JB-1424-2-8 whichexpresses Eagan Tbp2 from E. coli.

Referring to FIG. 18, there is shown plasmid S-4368-3-3 which containsthe entire tbp2 gene from H. influenzae type b Eagan. FIG. 18illustrates plasmid JB-1424-2-8 and FIG. 19 shows the oligonucleotidesused. Plasmid JB-1424-2-8 was introduced into E. coli strain BL21/DE3 byelectroporation to generate E. coli strain JB-1437-4-1. Upon inductionwith IPTG or lactose, Tbp2 was expressed by E. coli JB-1437-4-1 as shownin FIG. 22. Lane 1, JB-1476-2-1 (T7/Eagan Tbp1) at t_(o) ; lane 2,JB-1476-2-1 at t=4 h induction; lane 3, molecular weight markers of 200kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDa and 31 kDa; lane 4, JB-1437-4-1(T7/Eagan Tbp2) at t_(o) ; lane 5, JB-1437-4-1 at t=4 h induction; lane6, JB -1607-1-1 (T7/SB12 Tbp2) at t_(o) ; lane 7, JB-1607-1-1 at t=4 hinduction.

Example 9

This Example illustrates the construction of plasmids which encode alipoprotein leader sequence before the Tbp2 sequence.

Oligonucleotides used for the construction of plasmids with lipoproteinleader sequences derived from E. coli lpp (SEQ ID NOS: 88 and 89), rlpB(SEQ ID NOS: 90 and 91), and pal (SEQ ID NOS: 92 and 93) preceeding Tbp2are shown in FIG. 20. Plasmids constructed and corresponding strainsgenerated are illustrated in Table 1 below.

Example 10

This Example illustrates the construction of plasmid JB-1600-1 whichexpresses SB12 Tbp2 from E. coli.

Plasmid DS-1047-1-2 (FIG. 21) contains the PCR-amplified SB12 tbp2 gene.The tbp2 gene was excised as a Nde I to EcoR I restriction fragment andinserted into the pT7-7 expression vector to generate plasmid JB-1600-1.Electroporation into BL21/DE3 cells yielded E. coli strain JB-1607-1-1which expresses SB12 Tbp2. Upon induction with IPTG or lactose, SB12Tbp2 was expressed, as shown in FIG. 22. Lane 1, JB-1476-2-1 (T7/EaganTbp1) at t_(o) ; lane 2, JB-1476-2-1 at t=4 h induction; lane 3,molecular weight markers of 200 kDa, 116 kDa, 97.4 kDa, 66 kDa, 45 kDaand 31 kDa; lane 4, JB-1437-4-1 (T7/Eagan Tbp2) at t_(o) ; lane 5,JB-1437-4-1 at t=4 h induction; lane 6, JB-1607-1-1 (T7/SB12 Tbp2) att_(o) ; lane 7, JB-1607-1-1 at t=4 h induction.

Example 11

This Example illustrates the extraction and purification of Tbp1 andTbp2.

The purification scheme for Tbp1 and Tbp2 is shown in FIG. 23. Bothrecombinant proteins are expressed as inclusion bodies in E. coli andthe purification schemes are identical. Cells from a 500 ml culture,prepared as described in Example 7 for Tbp1 and in Example 8 for Tbp2,were resuspended in 50 ml of 50 mM Tris-HCl, pH 8.0, and disrupted bysonication (3×10 min, 70% duty circle). The extract was centrifuged at20,000×g for 30 min and the resultant supernatant which contained>95% ofthe soluble E. coli proteins was discarded.

The remaining pellet (FIG. 23, PPT₁) was further extracted in 50 ml of50 mM Tris, pH 8.0 containing 0.5% Triton X-100 and 10 mM EDTA. Aftercentrifugation at 20,000×g for 30 min, the supernatant containingresidual soluble proteins and the majority of the membrane proteins, wasdiscarded. The resultant pellet (FIG. 23, PPT₂) obtained after the aboveextraction, contained the inclusion bodies. The Tbp1 and Tbp2 proteinswere solubilized in 50 mM Tris, pH 8.0, containing 0.1% SDS and 5 mMDTT. After centrifugation, the resultant supernatant was furtherpurified on a Superdex 200 gel filtration column equilibrated in 50 mMTris, pH 8.0, containing 0.1% SDS and 5 mM DTT. The fractions wereanalysed by SDS PAGE and those containing purified Tbp1 or Tbp2 weredialysed overnight at 4° C. against 50 mM Tris, pH 8.0 and thencentrifuged at 20,000×g for 30 min. The protein remained soluble underthese conditions and the purified Tbp1 and Tbp2 were stored at -20° C.

The SDS-PAGE analysis of the purification process is shown in FIG. 24.Lanes 1, prestained molecular weight protein markers (106, 80, 49.5,32.5, 27.5, 18.5 kDa); lanes 2, E. coli whole cell lysates; lanes 3,solubilized inclusion bodies; lanes 4, purified Tbp1 or Tbp2.

Example 12

This Example illustrates immunogenicity studies of recombinant Tbp1 andTbp2 in mice.

Groups of five Balb/c mice were injected subcutaneously (s.c.) on days1, 29 and 43 with purified rTbp1 or rTbp2 (1 μg to 10 μg), prepared asdescribed in Example 11, in the presence of ALPO₄ (1.5 mg per dose).Blood samples were taken on days 14, 28, 42 and 56 for analysis of theanti-rTbp1 and anti-rTbp2 antibody titers by EIA. The results of theimmunogenicity studies are illustrated in FIG. 25.

Example 13

This Example illustrates the development of EIAs for determination ofanti-rTbp1 and anti-rTbp2 antibodies in mouse sera.

Anti-rTbp1 and anti-rTbp2 antibody titres were determined essentially asdescribed by Panezutti et al. (1993). Microtiter wells were coated with0.5 μg of rTbp1 or rTbp2, prepared as described in Example 11, for 16 hat room temperature, then blocked with 0.1% (w/v) BSA in PBS. The serawere serially diluted, added to the wells, then incubated for one hourat room temperature. Affinity-purified F(ab')₂ fragments of goatanti-mouse IgG (Fc specific) antibody conjugated to horseradishperoxidase were used as second antibody. The reactions were developedusing tetramethylbenzidine (TMB/H₂ O₂) and the absorbance was measuredat 450 nm (using 540 nm as a reference wavelength) in a Flow MultiskanMCC microplate reader. The reactive titer of an antiserum was defined asthe reciprocal of the dilution consistently showing a two-fold increasein absorbance over that obtained with the pre-immune serum sample.

Example 14

This Example illustrates the cross-reactivity of anti-Tbp1 antisera,produced by immunization with recombinant Eagan Tbp1, with variousstrains of H. influenzae.

Whole cell lysates of H. influenzae strains grown in BHI mediasupplemented with NAD and heme (Harkness et al., 1992) ±EDDA wereseparated by SDS PAGE gel, transferred to nitrocellulose membrane, andprobed with guinea pig anti-Tbp1 antisera raised to purified recombinantEagan Tbp1 (FIG. 26). Lane 1, BL21/DE3; lane 2, SB12 -EDDA; lane 3, SB12+EDDA; lane 4, SB29 -EDDA; lane 5, SB29 +EDDA; lane 6, SB33 -EDDA; lane7, SB33 +EDDA; lane 8, Eagan -EDDA; lane 9, Eagan +EDDA; lane 10, B.catarrhalis 4223 -EDDA; lane 11, B. catarrhalis 4223 +EDDA; lane 12, N.meningitidis 608 -EDDA; lane 13, N. meningitidis 608 +EDDA; lane 14,induced JB-1476-2-1 expressing recombinant Eagan Tbp1; lane 5, molecularweight markers. Specific ˜95 kDa bands reacted with the anti-Tbp1antisera in lanes 3, 4, 5, 7, 8 and 9, corresponding H. influenzaestrains SB12, SB29, SB33 and Eagan; ˜110 kDa bands in lanes 10 and 11,corresponding B. catarrhalis strain 4223; and ˜80 kDa bands in lanes 12and 13, corresponding to N. meningitidis 608.

Example 15

This Example illustrates the cross-reactivity of anti-Tbp2 antisera,produced by immunization with recombinant Eagan Tbp2, with variousstrains of H. influenzae.

Whole cell lysates of H. influenzae strains grown in BHI mediasupplemented with NAD and heme (Harkness et al., 1992) ±EDDA wereseparated on an SDS PAGE gel, transferred to nitrocellulose membrane,and probed with guinea pig anti-Tbp2 antisera raised to purifiedrecombinant Eagan Tbp2 (FIG. 27). Lane 1, molecular weight markers; lane2, induced JB-1437-4-1 expressing recombinant Eagan Tbp2; lane 3, SB12-EDDA; lane 4, SB12 +EDDA; lane 5, SB29 -EDDA; lane 6, SB29 +EDDA; lane7, SB30 -EDDA; lane 8, SB30 +EDDA; lane 9, SB32 -EDDA; lane 10, SB33-EDDA; lane 11, SB33 +EDDA; lane 12, PAK -EDDA; lane 13, PAK +EDDA; lane14, Eagan -EDDA; lane 15, Eagan +EDDA. Specific bands of about 60-70 kDawere reactive with the anti-Tbp2 antisera in lanes 3, 6, 7, 8, 13, 14and 15, corresponding to Haemophilus strains SB12, SB29, SB30, PAK andEagan.

Example 16

This Example illustrates the synthesis of synthetic peptidescorresponding to conserved regions in Tbp2 and Tbp1.

The deduced amino acid sequences of Tbp1 and Tbp2 were compared as shownin FIGS. 14 and 15 respectively. This comparison identified regions ofamino acid sequence conservation within the transferrin receptordescribed above and, as shown in Tables 2 and 3, peptides weresynthesized containing a portion of the transferrin receptor. Suchsynthesis may be effected by expression in a suitable host ofrecombinant vectors containing nucleic acid encoding said peptides or bystandard peptide synthesis.

Briefly, peptides were synthesized using an ABI 430A peptide synthesizerand optimized t-Boc chemistry using the conditions recommended by themanufacturer, and peptides were cleaved from the resin usinghydrofluoric acid (HF). The peptides were purified by reverse-phase highperformance liquid chromatography (RP-HPLC) on a Vydac C4semi-preparative column (1×30 cm) using a 15 to 55% acetonitrilegradient in 0.1% trifluoryl acetic acid (TFA) developed over 40 minutesat a flow rate of 2 ml/minute. All synthetic peptides used inbiochemical and immunological studies were >95% pure as judged byanalytical HPLC. Amino acid composition analyses were performed on aWaters Pico-Tag system and were in good agreement with the theoreticalcompositions.

Example 17

This Example illustrates the immunogenicity of synthetic peptides intest animals.

Guinea pigs were immunized intramuscularly with 100 μg of peptide,prepared as described in Example 16, emulsified in Freund's completeadjuvant on day 0 followed by boosters on days +14 and +28 using thesame amount of peptide emulsified in Freund's incomplete adjuvant. Serasamples were obtained on day 42 + and antibody titres determined byenzyme-linked immunosorbent assay (ELISA). Briefly, microtiter wells(Nunc-Immunoplate, Nunc, Denmark) were coated with 500 ng of any oneparticular peptide in 50 μL of coating buffer (15 mM Na₂ CO₃, 35 mMNaHCO₃, pH 9.6) for 16 hours at room temperature. The plates were thenblocked with 0.1% (w/v) BSA in phosphate buffer saline (PBS) for 30minutes at room temperature. The antisera were serially diluted, addedto the wells and incubated for 1 hour at room temperature. After removalof the antisera, the plates were washed five times with PBS containing0.1% (w/v) Tween-20 and 0.1% (w/v) BSA. F(ab')₂ from goat anti-guineapig IgG antibodies conjugated to horseradish peroxidase (JacksonImmunoResearch Labs Inc., Pennsylvania) were diluted (1/8,000) withwashing buffer, and added onto the microtiter plates. After 1 hour ofincubation at room temperature, the plates were washed five times withthe washing buffer. The plates were developed using the substratetetramethylbenzidine (TMB) in H₂ O₂ (ADI, Toronto), the reaction wasstopped with 1N H₂ SO₄ and the optical density was measured at 450 nmusing a Titretek Multiskan II (Flow Labs., Virginia). Two irrelevantpeptides of 32 amino acid residues were included as negative controls inthese ELISAs. Assays were performed in triplicate, and the reactivetiter of each antiserum was defined as the dilution consistently showinga 2-fold increase in absorbance value over those obtained from thenegative controls. The antisera raised in guinea pigs were monospecificfor the peptide used for immunization. The titres of the sera obtainedfollowing immunization are shown in Table 4.

Peptides of the present invention comprise single copies of any of thoseshown in Tables 2 and 3 or peptides containing multiple copies ofanalogs thereof. A peptide may further comprise multiples of differentpeptides selected from those shown in Tables 2 and 3 or analogs thereofand include suitable carrier molecules. It is preferred that thepeptides from conserved regions be used to develop antibodies because animmuno- or other type of binding assay can then be used to detectseveral species of Haemophilus. Tables 2 and 3 therefore set out severalother conserved regions of transferrin receptor to identify otherpeptides which would be useful in diagnosis, immunization and medicaltreatment.

Example 18

This Example describes the ability of antiserum raised against peptidescorresponding to conserved portions of transferrin receptor to recognizethe transferrin receptor of Branhamella catarrhalis.

Guinea pigs were immunized with peptide, corresponding to conservedportions of transferrin receptor, and antisera obtained are described inExample 17. A whole-cell extract of Branhamella catarrhalis wasimmunoblotted with the peptide-specific antiserum which specificallyrecognized the transferrin receptor from this bacterium. Anti-peptideantiserum from a guinea pig immunized with the Tbp2 N-terminal peptideand peptide TBP2-25 specifically recognized Tbp2 protein fromBranhamella catarrhalis and recombinant Tbp2 expressed by plasmid clonepBHIT2 in E. coli. Clone pBHIT2 expresses a truncated version of Tbp2starting at amino acid 80. (i.e. NKKFYSG SEQ ID NO: 105). Therefore, theTbp2 protein from pBHIT2 can only be recognized by antibodies raisedagainst the second epitope LEGGFYGP (TBP2-25). This analysis shows thatpeptides corresponding to conserved sequences between transferrinreceptor are useful in detecting most, if not all, bacteria that producetransferrin receptor and as components in immunogenic compositions,including vaccines to produce an immune response against transferrinreceptor and protect against diseases caused by such bacteria.

The sera from these rabbits were tested by ELISA against a peptideincorporating the sequence LEGGFYGP (SEQ ID NO:74) or against H.influenzae strain DL63, Tbp2. ELISA plates were coated with the peptideor the protein then blocked with 5% skim milk. Serial two-fold dilutionsof sera in phosphate buffered saline, 0.05% tween-20, and 1% dried milkwere incubated on the plates for two hours at 37° C., following whichthe plates were washed five times in phosphate buffered saline with0.05% tween-20. Washed plates were probed with a horse-radish peroxidase(HRPO)-conjugated donkey anti-rabbit IgG for 30 minutes at roomtemperature, then washed five times in phosphate buffered saline with0.05% tween-20. HRPO-substrate was added to all wells for 30 minutes atroom temperature in the dark, then color developemnt was halted by theaddition of 50 ul 1M sulphuric acid. Color was measured by determiningabsorbance at 450 nm.

Example 19

This Example illustrates the generation of H. influenzae strains that donot produce transferrin receptor.

A 2.55 Eco RI fragment of the insert from pBHIT1 was subcloned into theEco RI site of pUC4K, resulting in removal of the Tn903 kanamycinresistance (kan) cassette from this vector (pUHIT1; FIG. 28). Thissubcloning step facilitated the subsequent insertion of either a HincIIor PstI pUC4K fragment containing the kan cassette into the Hind III orPst I sites of pUHIT1 as both are unique sites in this construction toproduce pUHIT1KFH and pUHIT1KFP, FIG. 28. Following digestion with EcoRI to remove the interrupted gene sequences, the constructs wereintroduced into the H. influenzae wild type genome by transformationusing M-IV media as described previously (Barcak et al., 1991) andtransformants were selected on BHINH agar containing 20 μg/ml kanamycin.

Example 20

This Example illustrates the construction of polioviruses expressing anepitope of a transferrin receptor.

A cDNA clone of bases 1175 to 2956 of the poliovirus type 1, Mahoneystrain (PV1-M) genome was cut with restriction enzymes Sau I and HindIII. These enzymes excise a fragment containing bases 2754 to 2786,which encodes PV1-M amino acids 1094 to 1102, as shown in FIG. 29. Inthis application, we use the four-digit code for poliovirus amino-acids;for example, 1095 is amino acid 95 of capsid protein VP1. New hybridcDNA clones encoding both poliovirus and transferrin receptor amino-acidsequences were constructed by replacing the excised fragment withsynthetic oligonucleotides coding for amino acids from H. influenzaeTbp2. The new hybrid cDNA clones were cut with restriction enzymes Nhe Iand SnaB I, which excise a hybrid fragment, including the transferrinreceptor DNA sequences, from poliovirus base 2471 to 2956. A cDNA clone,for example pT7XLD or pT7CMCB, of the entire genome of PV1-M was cutwith Nhe I and SnaBI to excise a fragment from poliovirus base 2471 to2956. This was then replaced with a hybrid fragment including thetransferrin receptor DNA sequences to produce a hybrid cDNA clone of thegenome of PV1-M with bases 2754 to 2786 replaced by bases encoding ahybrid BC loop including transferrin receptor amino acids, as shown inFIG. 29.

The plasmid pT7XLD and clones derived from pT7XLD, such as pT7CMCB,contain a promoter sequence for the enzyme T7RNA polymerase at the 5'end of the PV1-M cDNA. RNA transcripts of the PV1-M cDNA, including anybases encoding transferrin receptor amino acids, were prepared using T7RNA polymerase as described by van der Werf et al. Transfection of Verocells with these RNA transcripts produced four viable hybrid viruses,designated PV1TBP2A, PV1TBP2B, PV1TBP2C and PV1TBP2D. Transfection withtranscripts of pT7CMCB yielded a transfection-derived wild-typepoliovirus designated PV1XLD (FIG. 29).

The antigenic characteristics of PV1TBP2A, PV1TBP2B, PV1TBP2C andPV1TBP2D are shown in Table 5. All were neutralized by guinea-pigantisera raised against a peptide incorporating the sequence LEGGFYGP(SEQ ID NO: 74), indicating that the viruses expressed this sequence inan antigenically recognisable form. To produce the antisera femaleguinea pigs were immunized IM with a 500 ul volume containing 200 ugpeptide formulated in aluminum phosphate (3 mg/ml). Animals wereimmunized on days 1, 14, 28 and 42 and bled on days 0, 28, 42 and 56.Sera were from the day 56 bleed. PV1TBP2A and PV1TBP2B were alsoneutralized by rabbit antisera raised against H. influenzae strain DL63Tbp2, indicating that at least these two viruses expressed the sequencein a form recognisable to antibodies raised against the protein. Allviruses were neutralisable by anti-PV1 sera, indicating that the changesin polio neutralization antigenic site I had not significantly affectedother antigenic sites on the viruses.

Example 21

This Example illustrates the use of poliovirus hybrids to induce hightiter antisera against Tbp2.

Rabbits were inoculated with CsCl-purified PV1TBP2A (rabbits #40, 41,42). Note that, although the viruses used were live, poliovirus does notreplicate in rabbits and that any response observed is effectively theresponse to an inactivated antigen. On day 1, rabbits were inoculatedwith 1 ug of virus in Freund's complete adjuvant subcutaneously on theback, and, on day 14, the rabbits were boosted with 1 ug of virus inFreund's incomplete adjuvant inoculated subcutaneously on the back. Therabbits were bled on day 0 (prebleed) and on day 27. The dose of virusper inoculation was 2.5×10⁸ pfu, which was determined from A₂₆₀ valuesto be approximately 3.0×10¹¹ virions. This equivalent to 0.5 pmol ofvirus or 30 pmol of the LEGGFYG (SEQ ID NO: 74) epitope, since eachvirion expresses 60 copies of the epitope.

SUMMARY OF THE DISCLOSURE

In summary of this disclosure, the present invention provides purifiedand isolated DNA molecules containing transferrin receptor genes, thesequences of these transferrin receptor genes and the derived amino acidsequences thereof. The invention also provides peptides corresponding toportions of the transferrin receptor. The genes, DNA sequences,recombinant proteins and peptides are useful for diagnosis, immunizationand the generation of diagnostic and immunological reagents. Vaccinesbased upon expressed recombinant Tbp1 and/or Tbp2, portions thereof, orpeptides derived from the provided sequences can be prepared forprevention of diseases caused by bacterial pathogens that producetransferrin receptor. Modifications are possible within the scope ofthis invention.

                  TABLE 1                                                         ______________________________________                                        leader     1st residue                                                                             plasmid     strain                                       ______________________________________                                        E. coli lpp                                                                              Cys       JB-1360-1R-10                                                                             JB-1407-1-1                                  E. coli lpp                                                                              Ser       JB-1366-1R-7                                                                              JB-1407-3-1                                  E. coli pal                                                                              Cys       JB-1360-3-10                                                                              JB-1407-2-1                                  E. coli pal                                                                              Ser       JB-1366-3R-5                                                                              JB-1407-4-4                                  E. coli rlpB                                                                             Cys       JB-1399-1   JB-1437-1-1                                  E. coli rlpB                                                                             Ser       JB-1378-7   JB-1407-5-1                                  ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________    PREDICTED ANTIGENIC Tbp1 PEPTIDES                                             PEPTIDE                                                                             RESIDUES.sup.1                                                                       SEQUENCES                 SEQ ID NO:                             __________________________________________________________________________    TBP1-N                                                                               1-36  AETQSIKDTKEAISSEVDTQSTEDSELETISVTAEK                                                                    13                                     TBP1-2                                                                               31-66 SVTAEKVRDRKDNEVTGLGKIIKTSESISREQVLNI                                                                    14                                     TBP1-3                                                                               59-94 SREQVLNIRDLTRYDPGISVVEQGRGASSGYSIRGM                                                                    15                                     TBP1-4                                                                               88-123                                                                              GYSIRGMDRNRVALLVDGLPQTQSYVVQSPLVARSG                                                                    16                                     TBP1-5                                                                              117-152                                                                              PLVARSGYGTGAINEIEYENVKAVEISKGGSSSEYG                                                                    17                                     TBP1-6                                                                              147-182                                                                              SSSEYGNGALAGSVTFQSKSAADILEGDKSWGIQTK                                                                    18                                     TBP1-7                                                                              179-214                                                                              GIQTKNAYSSKNKGFTHSLAVAGKQGGFEGVAIYTH                                                                    19                                     TBP1-8                                                                              208-243                                                                              GVAIYTHRNSIETQVHKDALKGVQSYDRFIATTEDQ                                                                    20                                     TBP1-9                                                                              236-271                                                                              IATTEDQSAYFVMQDECLDGYDKCKTSPKRPATLST                                                                    21                                     TBP1-10                                                                             266-301                                                                              PATLSTQRETVSVSDYTGANRIKPNPMKYESQSWFL                                                                    22                                     TBP1-11                                                                             293-328                                                                              YESQSWFLRGGYHFSEQHYIGGIFEFTQQKFDIRDM                                                                    23                                     TBP1-12                                                                             322-357                                                                              KFDIRDMTFPAYLRPTEDKDLQSRPFYPKQDYGAYQ                                                                    24                                     TBP1-13                                                                             352-387                                                                              DYGAYQHIGDGRGVKYASGLYFDEHHRKQRVGIEYI                                                                    25                                     TBP1-14                                                                             383-418                                                                              GIEYIYENKNKAGIIDKAVLSANQQNIILDSYMRHT                                                                    26                                     TBP1-15                                                                             412-447                                                                              DSYMRHTHCSLYPNPSKNCRPTLDKPYSYYHSDRNV                                                                    27                                     TBP1-16                                                                             443-478                                                                              SDRNVYKEKHNMLQLNLEKKIQQNWLTHQIAFNLGF                                                                    28                                     TBP1-17                                                                             469-504                                                                              THQIAFNLGFDDFTSALQHKDYLTRRVIATASSISE                                                                    29                                     TBP1-M                                                                              498-534                                                                              TASSISEKRGEARRNGLQSSPYLYPTPKAELVGGDLC                                                                   30                                     TBP1-19                                                                             528-563                                                                              LVGGDLCNYQGKSSNYSDCKVRLIKGKNYYFAARNN                                                                    31                                     TBP1-20                                                                             558-593                                                                              FAARNNMALGKYVDLGLGMRYDVSRTKANESTISVG                                                                    32                                     TBP1-21                                                                             588-623                                                                              STISVGKFKNFSWNTGIVIKPTEWLDLSYRLSTGFR                                                                    33                                     TBP1-22                                                                             618-653                                                                              LSTGFRNPSFAEMYGWRYGGKDTDVYIGKFKPETSR                                                                    34                                     TBP1-23                                                                             648-683                                                                              KPETSRNQEFGLALKGDFGNIEISHFSNAYRNLIAF                                                                    35                                     TBP1-24                                                                             677-712                                                                              YRNLIAFAEELSKNGTTGKGNYGYHNAQNAKLVGVN                                                                    36                                     TBP1-25                                                                             706-741                                                                              AKLVGVNITAQLDFNGLWKRIPYGWYATFAYNRVKV                                                                    37                                     TBP1-26                                                                             735-770                                                                              AYNRVKVKDQKINAGLASVSSYLFDAIQPSRYIIGL                                                                    38                                     TBP1-27                                                                             764-799                                                                              SRYIIGLDYDHPSNTWGIKTMFTQSKAKSQNELLGK                                                                    39                                     TBP1-28                                                                             794-829                                                                              NELLGKRALGNNSRNVKSTRKLTRAWHILDVSGYYM                                                                    40                                     TBP1-29                                                                             825-854                                                                              SGYYMVNRSILFRLGVYNLLNYRYVTWEAV                                                                          41                                     TBP1-30                                                                             843-865                                                                              LLNYRYVTWEAVRQTAQGAEFDI   42                                     TBP1-31                                                                              42-50 DNEVTGLGK                 43                                     TBP1-32                                                                              61-76 EQVLNIRDLTRYDPGI          44                                     TBP1-33                                                                              61-95 EQVLNIRDLTRYDPGISVVEQGRGASSGYSIRGMD                                                                     45                                     TBP1-34                                                                             128-146                                                                              GAINEIEYENVKAVEISKG       46                                     TBP1-35                                                                             155-161                                                                              GALAGSV                   47                                     TBP1-1                                                                               1-14  AETQSIKDTKEAISC.sup.2     48                                     __________________________________________________________________________     .sup.1. Residue number from the sequence of Tbp1 of H. influenzae type b      strain Eagan (as shown in FIG. 8).                                            .sup.2. Cysteine added to facilitate coupling to a carrier protein, for       example KLH.                                                             

                                      TABLE 3                                     __________________________________________________________________________    PREDICTED CONSERVED ANTIGENIC Tbp2 PEPTIDES                                   PEPTIDE                                                                             RESIDUES.sup.1                                                                       SEQUENCES                 SEQ ID NO:                             __________________________________________________________________________    TBP2-1                                                                               18-31 CSGGGSFDVDNVSN            49                                     TBP2-2                                                                              231-261                                                                              LEGGFYGPKGEELGFRFLAGDKKVFGVFSAK                                                                         50                                     TBP2-3                                                                              358-380                                                                              TVGKKTYQVEACCSNLSYVKFGM   51                                     TBP2-4                                                                              527-549                                                                              ATVKGAFYGPKASELGGYFTYNG   52                                     TBP2-5                                                                               1-36  MKLAALNLFDRNKPSLLNEDSYMIFSSRSTIEEDV                                                                     53                                     TBP2-6                                                                               29-64 STIEEDVKNDNQNGEHPIDSIVDPRAPNSNENRHG                                                                     54                                     TBP2-7                                                                               57-92 SNENRHGQKYVYSGLYYIQSWSLRDLPNKKFYSGY                                                                     55                                     TBP2-8                                                                               85-120                                                                              KKFYSGYYGYAYYFGNTTASALPVGGVATYKGTWS                                                                     56                                     TBP2-9                                                                              113-148                                                                              TYKGTWSFITAAENGKNYELLRNSGGGQAYSRRSA                                                                     57                                     TBP2-10                                                                             141-176                                                                              AYSRRSATPEDIDLDRKTGLTSEFTVNFGTKKLTG                                                                     58                                     TBP2-11                                                                             169-204                                                                              GTKKLTGGLYYNLRETDANKSQNRTHKLYDLEADV                                                                     59                                     TBP2-12                                                                             197-232                                                                              YDLEADVHSNRFRGKVKPTKKESSEEHPFTSEGTL                                                                     60                                     TBP2-13                                                                             225-260                                                                              FTSEGTLEGGFYGPEGQELGGKFLAHDKKVLGVFS                                                                     61                                     TBP2-14                                                                             253-288                                                                              KVLGVFSAKEQQETSENKKLPKETLIDGKLTTFKT                                                                     62                                     TBP2-15                                                                             281-316                                                                              KLTTFKTTNATANATTDATTSTTASTKTDTTTNAT                                                                     63                                     TBP2-16                                                                             309-344                                                                              DTTTNATANTENFTTKDIPSLGEADYLLIDNYPVP                                                                     64                                     TBP2-17                                                                             337-372                                                                              IDNYPVPLFPESGDFISSKHHTVGKKTYQVEACCS                                                                     65                                     TBP2-M                                                                              360-406                                                                              CSNLSYVKFGMYYEAPPKEEEKEKEKDKDKEKEKQA                                                                    66                                     TBP2-19                                                                             393-428                                                                              KEKDKDKEKEKQATTSIKTYYQFLLGLRTPSSEIP                                                                     67                                     TBP2-20                                                                             421-456                                                                              TPSSEIPKEGSAKYHGNWFGYISDGETSYSASGDK                                                                     68                                     TBP2-21                                                                             449-484                                                                              YSASGDKERSKNAVAEFNVNFAEKTLTGELKRHDT                                                                     69                                     TBP2-22                                                                             477-512                                                                              ELKRHDTQNPVFKINATFQSGKNDFTGTATAKDLA                                                                     70                                     TBP2-23                                                                             505-540                                                                              ATAKDLAIDGKNTQGTSKVNFTATVNGAFYGPHAT                                                                     71                                     TBP2-24                                                                             533-559                                                                              FYGPHATELGGYFTYNGNNPTDKNSS                                                                              72                                     TBP2-C                                                                              553-581                                                                              CPTDKNSSSNSEKARAAVVFGAKKQQVETTK                                                                         73                                     TBP2-25                                                                             231-238                                                                              LEGGFYGP                  74                                     TBP2-26                                                                              18-25 CSGGGSFD                  75                                     TBP2-27                                                                             130-134                                                                              YVYSGL                    76                                     TBP2-28                                                                             345-355                                                                              CCSNLSYVKFG               77                                     TBP2-29                                                                             401-407                                                                              FLLGHRT                   78                                     TBP2-30                                                                             450-456                                                                              EFNVDF                    79                                     TBP2-31                                                                             485-491                                                                              NAFTGTA                   80                                     TBP2-32                                                                             516-522                                                                              VNGAFYG                   81                                     TBP2-33                                                                             527-532                                                                              ELGGYF                    82                                     TBP2-34                                                                             562-566                                                                              VVFGAR                    83                                     TBP2-35                                                                             562-568                                                                              VVFGAK                    84                                     TBP2-36                                                                             231-238                                                                              LEGGFYG                   85                                     __________________________________________________________________________     .sup.1. Residue number from the sequence of Tbp2 of H. influenzae type B      Eagan strain (as shown in FIG. 9).                                       

                                      TABLE 4                                     __________________________________________________________________________    Guinea pig antibody responses to Tbp1 and Tbp2 peptides                       PEPTIDE                                                                             SEQ ID                                                                             SEQUENCES                 TITRE                                    __________________________________________________________________________    TBP1-N                                                                              13   AETQSIKDTKEAISSEVDTQSTEDSELETISVTAEK                                                                    500                                      TBP1-M                                                                              30   TASSISEKRGEARRNGLQSSPYLYPTPKAELVGGDLC                                                                   1562500                                  TBP1-1                                                                              48   AETQSIKDTKEAISC           <100                                     TBP2-1                                                                              49   CSGGGSFDVDNVSN            2500                                     TBP2-2                                                                              50   LEGGFYGPKGEELGFRFLAGDKKVFGVFSAK                                                                         12500                                    TBP2-3                                                                              51   TVGKKTYQVEACCSNLSYVKFGM   62500                                    TBP2-4                                                                              52   ATVKGAFYGPKASELGGYFTYNG   <100                                     TBP2-M                                                                              66   CSNLSYVKFGMYYEAPPKEEEKEKEKDKDKEKEKQA                                                                    62500                                    TBP2-C                                                                              73   CPTDKNSSSNSEKARAAVVFGAKKQQVETTK                                                                         312500                                   __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Neutralizing activity of anti-Tbp2 and anti-peptide sera                      against polio/Tbp2 hybrid viruses                                                       Neutralizing Titre v. Virus.sup.b                                   Sera.sup.a                                                                              PV1TBP2A                                                                             PV1TBP2B                                                                             PV1TBP2C                                                                             PV1TBP2D                                                                             PV1XLD                                  __________________________________________________________________________    Rb @PV1   >40,9600                                                                             25,844 20,480 16,763 >40,960                                 Rb 516 D0 <4     <4     <4     <4     <4                                      Rb 516 D42                                                                              40     20     <4     <4     <4                                      GP561, 562 D0 pool                                                                      <4     <4     <4     <4     <4                                      GP 561 D56                                                                              >2048  >2048  >2048  1164   <4                                      GP 562 D56                                                                              >2048  >2048  25     10     <4                                      GP558, 559, 560                                                                         <4     <4     <4     <4     <4                                      D56 pool                                                                      __________________________________________________________________________     .sup.a Rb @PV1 is pool of rabbit immune sera raised against PV1XLD. Rabbi     516 was immunised with three successive 3 μg dses of recombinant H.        influenzae DL63 transferrin binding protein 2 on days 1, 14 and 28. Serum     was collected on days 0 (D0) and 42 (D42). Guineapigs were immunized with     four successive doses of 200 μg of peptide on days 1, 14, 28 and 42.       Sera were collected on day 0 (D0) and day 56 (D56). GuineaPigs 561 and 56     received a peptide  containing the sequence LEGGFYGP (SEQ ID NO:74).          Guineapigs 558, 559 and 556 received a control peptide with an unrelated      sequence.                                                                     .sup.b Titre is the inverse dilution of serum giving a 50% endpoint in a      virus neutralization assay versus 100 TCID.sub.50 of virus.              

                  TABLE 6                                                         ______________________________________                                        Peptide-specific IgG titres of rabbits immunised with                         PV1TBP2A or PV1TBP2B                                                                         PEPTIDE-SPECIFIC                                                              IgG TITRES.sup.a                                               RABBIT (ANTIGEN) PREBLEED  DAY 27                                             ______________________________________                                        40 (PV1TBP2A)    <20       640                                                41 (PV1TBP2A)    <20       640                                                42 (PV1TBP2A)    <20       2560                                               43 (PV1TBP2B)    <20       160                                                44 (PV1TBP2B)    <20       1280                                               45 (PV1TBP2B)    <20       1280                                               10 (PV1 Mahoney)           <20.sup.b                                          11 (PV1 Mahoney)           <20                                                ______________________________________                                         .sup.a Titres are the reciprocal of the greatest dilution of sera giving      an A.sub.450 of at least twice the background value. The background value     was the mean A.sub.450 of wells assayed in the absence of rabbit sera.        .sup.b Titres for rabbits 10 and 11 refer to sera taken on day 42 after       three immunisations with PV1 Mahoney. Rabbits 10 and 11 were immunised as     rabbits 40 to 45, except that an additional booster dose was administered     on day 28.                                                               

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    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 147                                                (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4699 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: join(10..1940, 1957..4696)                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       TATAACTCAATGAAATCTGTACCTCTTATCTCTGGTGGACTTTCCTTT48                            MetLysSerValProLeuIleSerGlyGlyLeuSerPhe                                       1510                                                                          TTACTAAGTGCTTGTAGCGGAGGGGGGTCTTTTGATGTAGATAACGTC96                            LeuLeuSerAlaCysSerGlyGlyGlySerPheAspValAspAsnVal                              152025                                                                        TCTAATACCCCCTCTTCTAAACCACGTTATCAAGACGATACTTCAAGT144                           SerAsnThrProSerSerLysProArgTyrGlnAspAspThrSerSer                              30354045                                                                      TCAAGAACAAAATCTAAATTGGAAAAGTTGTCCATTCCTTCTTTAGGG192                           SerArgThrLysSerLysLeuGluLysLeuSerIleProSerLeuGly                              505560                                                                        GGAGGGATGAAGTTAGCGGCTCTGAATCTTTTTGATAGGAACAAACCT240                           GlyGlyMetLysLeuAlaAlaLeuAsnLeuPheAspArgAsnLysPro                              657075                                                                        AGTCTCTTAAATGAAGATAGCTATATGATATTTTCCTCACGTTCTACG288                           SerLeuLeuAsnGluAspSerTyrMetIlePheSerSerArgSerThr                              808590                                                                        ATTGAAGAGGATGTTAAAAATGACAATCAAAACGGCGAGCACCCTATT336                           IleGluGluAspValLysAsnAspAsnGlnAsnGlyGluHisProIle                              95100105                                                                      GACTCAATAGTCGATCCTAGAGCACCAAATTCAAACGAAAATCGTCAT384                           AspSerIleValAspProArgAlaProAsnSerAsnGluAsnArgHis                              110115120125                                                                  GGACAAAAATATGTATATTCAGGGCTTTATTATATTCAATCGTGGAGT432                           GlyGlnLysTyrValTyrSerGlyLeuTyrTyrIleGlnSerTrpSer                              130135140                                                                     CTAAGAGATTTACCAAATAAAAAGTTTTATTCAGGTTACTATGGATAT480                           LeuArgAspLeuProAsnLysLysPheTyrSerGlyTyrTyrGlyTyr                              145150155                                                                     GCGTATTACTTTGGCAATACAACTGCCTCTGCATTACCTGTAGGTGGC528                           AlaTyrTyrPheGlyAsnThrThrAlaSerAlaLeuProValGlyGly                              160165170                                                                     GTAGCAACGTATAAAGGAACTTGGAGCTTCATCACCGCAGCTGAAAAT576                           ValAlaThrTyrLysGlyThrTrpSerPheIleThrAlaAlaGluAsn                              175180185                                                                     GGCAAGAATTATGAATTGTTAAGAAATTCTGGTGGCGGTCAAGCTTAT624                           GlyLysAsnTyrGluLeuLeuArgAsnSerGlyGlyGlyGlnAlaTyr                              190195200205                                                                  TCTCGACGTAGTGCTACTCCAGAAGATATTGATTTAGATCGTAAGACG672                           SerArgArgSerAlaThrProGluAspIleAspLeuAspArgLysThr                              210215220                                                                     GGCTTAACAAGTGAATTTACTGTCAATTTTGGTACAAAAAAGCTCACT720                           GlyLeuThrSerGluPheThrValAsnPheGlyThrLysLysLeuThr                              225230235                                                                     GGAGGACTTTATTATAATTTACGTGAAACAGATGCTAATAAATCACAA768                           GlyGlyLeuTyrTyrAsnLeuArgGluThrAspAlaAsnLysSerGln                              240245250                                                                     AATAGAACACATAAACTCTACGATCTAGAAGCTGATGTTCATAGCAAC816                           AsnArgThrHisLysLeuTyrAspLeuGluAlaAspValHisSerAsn                              255260265                                                                     CGATTCAGGGGTAAAGTAAAGCCAACCAAAAAAGAGTCTTCTGAAGAA864                           ArgPheArgGlyLysValLysProThrLysLysGluSerSerGluGlu                              270275280285                                                                  CATCCCTTTACCAGCGAGGGAACATTAGAAGGTGGTTTTTACGGGCCT912                           HisProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyPro                              290295300                                                                     GAGGGTCAAGAATTAGGAGGAAAGTTTTTAGCTCACGACAAAAAAGTT960                           GluGlyGlnGluLeuGlyGlyLysPheLeuAlaHisAspLysLysVal                              305310315                                                                     TTGGGGGTATTTAGTGCCAAAGAACAGCAAGAAACGTCAGAAAACAAA1008                          LeuGlyValPheSerAlaLysGluGlnGlnGluThrSerGluAsnLys                              320325330                                                                     AAATTACCCAAAGAAACCTTAATTGATGGCAAGCTAACTACTTTTAAA1056                          LysLeuProLysGluThrLeuIleAspGlyLysLeuThrThrPheLys                              335340345                                                                     ACAACCAATGCAACAGCCAATGCAACAACCGATGCAACAACCAGTACA1104                          ThrThrAsnAlaThrAlaAsnAlaThrThrAspAlaThrThrSerThr                              350355360365                                                                  ACAGCCAGTACAAAAACCGATACAACAACCAATGCAACAGCCAATACA1152                          ThrAlaSerThrLysThrAspThrThrThrAsnAlaThrAlaAsnThr                              370375380                                                                     GAAAACTTTACGACAAAAGATATACCAAGTTTGGGTGAAGCTGATTAT1200                          GluAsnPheThrThrLysAspIleProSerLeuGlyGluAlaAspTyr                              385390395                                                                     CTTTTAATTGATAATTACCCTGTTCCTCTTTTCCCTGAGAGTGGTGAT1248                          LeuLeuIleAspAsnTyrProValProLeuPheProGluSerGlyAsp                              400405410                                                                     TTCATAAGTAGTAAGCACCATACTGTAGGAAAGAAAACCTATCAAGTA1296                          PheIleSerSerLysHisHisThrValGlyLysLysThrTyrGlnVal                              415420425                                                                     GAAGCATGTTGCAGTAATCTAAGCTATGTAAAATTTGGTATGTATTAT1344                          GluAlaCysCysSerAsnLeuSerTyrValLysPheGlyMetTyrTyr                              430435440445                                                                  GAAGCCCCACCTAAAGAAGAAGAAAAAGAAAAAGAAAAAGACAAAGAC1392                          GluAlaProProLysGluGluGluLysGluLysGluLysAspLysAsp                              450455460                                                                     AAAGAAAAAGAAAAACAAGCGACAACATCTATCAAGACTTATTATCAA1440                          LysGluLysGluLysGlnAlaThrThrSerIleLysThrTyrTyrGln                              465470475                                                                     TTCTTATTAGGTCTCCGTACTCCCAGTTCTGAAATACCTAAAGAAGGA1488                          PheLeuLeuGlyLeuArgThrProSerSerGluIleProLysGluGly                              480485490                                                                     AGTGCAAAATATCATGGTAATTGGTTTGGTTATATTAGTGATGGCGAG1536                          SerAlaLysTyrHisGlyAsnTrpPheGlyTyrIleSerAspGlyGlu                              495500505                                                                     ACATCTTACTCCGCCAGTGGTGATAAGGAACGCAGTAAAAATGCTGTC1584                          ThrSerTyrSerAlaSerGlyAspLysGluArgSerLysAsnAlaVal                              510515520525                                                                  GCCGAGTTTAATGTAAATTTTGCCGAGAAAACATTAACAGGCGAATTA1632                          AlaGluPheAsnValAsnPheAlaGluLysThrLeuThrGlyGluLeu                              530535540                                                                     AAACGACACGATACTCAAAATCCCGTATTTAAAATTAATGCAACCTTT1680                          LysArgHisAspThrGlnAsnProValPheLysIleAsnAlaThrPhe                              545550555                                                                     CAAAGTGGTAAGAATGACTTCACTGGTACAGCAACCGCAAAAGATTTA1728                          GlnSerGlyLysAsnAspPheThrGlyThrAlaThrAlaLysAspLeu                              560565570                                                                     GCAATAGATGGTAAAAATACACAAGGCACATCTAAAGTCAATTTCACG1776                          AlaIleAspGlyLysAsnThrGlnGlyThrSerLysValAsnPheThr                              575580585                                                                     GCAACAGTAAACGGGGCATTTTATGGTCCGCACGCTACAGAATTAGGC1824                          AlaThrValAsnGlyAlaPheTyrGlyProHisAlaThrGluLeuGly                              590595600605                                                                  GGTTATTTCACCTATAACGGAAACAATCCTACAGATAAAAATTCATCA1872                          GlyTyrPheThrTyrAsnGlyAsnAsnProThrAspLysAsnSerSer                              610615620                                                                     TCCAATTCAGAAAAGGCAAGAGCTGCCGTTGTGTTTGGAGCTAAAAAA1920                          SerAsnSerGluLysAlaArgAlaAlaValValPheGlyAlaLysLys                              625630635                                                                     CAACAAGTAGAAACAACCAAGTAATGGAATACTAAAAATGACTAAAAAA1969                         GlnGlnValGluThrThrLysMetThrLysLys                                             640645                                                                        CCCTATTTTCGCCTAAGTATTATTTCTTGTCTTTTAATTTCATGCTAT2017                          ProTyrPheArgLeuSerIleIleSerCysLeuLeuIleSerCysTyr                              650655660                                                                     GTAAAAGCAGAAACTCAAAGTATAAAAGATACAAAAGAAGCTATATCA2065                          ValLysAlaGluThrGlnSerIleLysAspThrLysGluAlaIleSer                              665670675680                                                                  TCTGAAGTGGACACTCAAAGTACAGAAGATTCAGAATTAGAAACTATC2113                          SerGluValAspThrGlnSerThrGluAspSerGluLeuGluThrIle                              685690695                                                                     TCAGTCACTGCAGAAAAAGTTAGAGATCGTAAAGATAATGAAGTAACT2161                          SerValThrAlaGluLysValArgAspArgLysAspAsnGluValThr                              700705710                                                                     GGACTTGGCAAAATTATAAAAACTAGTGAAAGTATCAGCCGAGAACAA2209                          GlyLeuGlyLysIleIleLysThrSerGluSerIleSerArgGluGln                              715720725                                                                     GTATTAAATATTCGTGATCTAACACGCTATGATCCAGGGATTTCAGTT2257                          ValLeuAsnIleArgAspLeuThrArgTyrAspProGlyIleSerVal                              730735740                                                                     GTAGAACAAGGTCGCGGTGCAAGTTCTGGATATTCTATTCGTGGTATG2305                          ValGluGlnGlyArgGlyAlaSerSerGlyTyrSerIleArgGlyMet                              745750755760                                                                  GACAGAAATAGAGTTGCTTTATTAGTAGATGGTTTACCTCAAACGCAA2353                          AspArgAsnArgValAlaLeuLeuValAspGlyLeuProGlnThrGln                              765770775                                                                     TCTTATGTAGTGCAAAGCCCTTTAGTTGCTCGTTCAGGATATTCTGGC2401                          SerTyrValValGlnSerProLeuValAlaArgSerGlyTyrSerGly                              780785790                                                                     ACTGGTGCAATTAATGAAATTGAATATGAAAATGTAAAGGCCGTCGAA2449                          ThrGlyAlaIleAsnGluIleGluTyrGluAsnValLysAlaValGlu                              795800805                                                                     ATAAGCAAGGGGGGGAGTTCTTCTGAGTATGGTAATGGAGCACTAGCT2497                          IleSerLysGlyGlySerSerSerGluTyrGlyAsnGlyAlaLeuAla                              810815820                                                                     GGTTCTGTAACATTTCAAAGCAAATCAGCAGCCGATATCTTAGAAGGA2545                          GlySerValThrPheGlnSerLysSerAlaAlaAspIleLeuGluGly                              825830835840                                                                  GACAAATCATGGGGAATTCAAACTAAAAATGCTTATTCAAGCAAAAAT2593                          AspLysSerTrpGlyIleGlnThrLysAsnAlaTyrSerSerLysAsn                              845850855                                                                     AAAGGCTTTACCCATTCTTTAGCTGTAGCAGGAAAACAAGGTGGATTT2641                          LysGlyPheThrHisSerLeuAlaValAlaGlyLysGlnGlyGlyPhe                              860865870                                                                     GAAGGGGTCGCCATTTACACTCACCGAAATTCAATTGAAACCCAAGTC2689                          GluGlyValAlaIleTyrThrHisArgAsnSerIleGluThrGlnVal                              875880885                                                                     CATAAAGATGCATTAAAAGGCGTGCAAAGTTATGATCGATTCATCGCC2737                          HisLysAspAlaLeuLysGlyValGlnSerTyrAspArgPheIleAla                              890895900                                                                     ACAACAGAGGATCAATCTGCATACTTTGTGATGCAAGATGAGTGTCTA2785                          ThrThrGluAspGlnSerAlaTyrPheValMetGlnAspGluCysLeu                              905910915920                                                                  GATGGTTATGACAAGTGTAAAACTTCACCCAAACGACCTGCGACTTTA2833                          AspGlyTyrAspLysCysLysThrSerProLysArgProAlaThrLeu                              925930935                                                                     TCCACCCAAAGAGAAACCGTAAGCGTTTCAGATTATACGGGGGCTAAC2881                          SerThrGlnArgGluThrValSerValSerAspTyrThrGlyAlaAsn                              940945950                                                                     CGTATCAAACCTAATCCAATGAAATATGAAAGCCAGTCTTGGTTTTTA2929                          ArgIleLysProAsnProMetLysTyrGluSerGlnSerTrpPheLeu                              955960965                                                                     AGAGGAGGTTATCATTTTTCTGAACAACACTATATTGGTGGTATTTTT2977                          ArgGlyGlyTyrHisPheSerGluGlnHisTyrIleGlyGlyIlePhe                              970975980                                                                     GAATTCACACAACAAAAATTTGATATCCGTGATATGACATTTCCCGCT3025                          GluPheThrGlnGlnLysPheAspIleArgAspMetThrPheProAla                              9859909951000                                                                 TATTTAAGGCCAACAGAAGACAAGGATTTACAAAGTCGCCCTTTTTAT3073                          TyrLeuArgProThrGluAspLysAspLeuGlnSerArgProPheTyr                              100510101015                                                                  CCAAAGCAAGATTATGGTGCATATCAACATATTGGTGATGGCAGAGGC3121                          ProLysGlnAspTyrGlyAlaTyrGlnHisIleGlyAspGlyArgGly                              102010251030                                                                  GTTAAATATGCAAGTGGGCTTTATTTCGATGAACACCATAGAAAACAG3169                          ValLysTyrAlaSerGlyLeuTyrPheAspGluHisHisArgLysGln                              103510401045                                                                  CGTGTAGGTATTGAATATATTTACGAAAATAAGAACAAAGCGGGCATC3217                          ArgValGlyIleGluTyrIleTyrGluAsnLysAsnLysAlaGlyIle                              105010551060                                                                  ATTGACAAAGCGGTGTTAAGTGCTAATCAACAAACATCATACTTGACA3265                          IleAspLysAlaValLeuSerAlaAsnGlnGlnThrSerTyrLeuThr                              1065107010751080                                                              GTTATATGCGACATACGCATTGCAGTCTTTATCCATAATCCAAGTAAG3313                          ValIleCysAspIleArgIleAlaValPheIleHisAsnProSerLys                              108510901095                                                                  AATTGCCGCCCAACACTTGATAAACCTTATTCATACTATCATTCTGAT3361                          AsnCysArgProThrLeuAspLysProTyrSerTyrTyrHisSerAsp                              110011051110                                                                  AGAAATGTTTATAAAGAAAAACATAACATGTTGCAATTGAATTTAGAG3409                          ArgAsnValTyrLysGluLysHisAsnMetLeuGlnLeuAsnLeuGlu                              111511201125                                                                  AAAAAAATTCAACAAAATTGGCTTACTCATCAAATTGCCTTCAATCTT3457                          LysLysIleGlnGlnAsnTrpLeuThrHisGlnIleAlaPheAsnLeu                              113011351140                                                                  GGTTTTGATGACTTTACTTCCGCACTTCAGCATAAAGATTATTTAACT3505                          GlyPheAspAspPheThrSerAlaLeuGlnHisLysAspTyrLeuThr                              1145115011551160                                                              CGACGTGTTATCGCTACGGCAAGTAGTATTTCAGAGAAACGTGGTGAA3553                          ArgArgValIleAlaThrAlaSerSerIleSerGluLysArgGlyGlu                              116511701175                                                                  GCAAGAAGAAATGGTTTACAATCAAGTCCTTACTTATACCCAACACCA3601                          AlaArgArgAsnGlyLeuGlnSerSerProTyrLeuTyrProThrPro                              118011851190                                                                  AAAGCAGAGTTGGTAGGAGGAGATCTTTGTAATTATCAAGGTAAGTCC3649                          LysAlaGluLeuValGlyGlyAspLeuCysAsnTyrGlnGlyLysSer                              119512001205                                                                  TCTAATTACAGTGACTGTAAAGTGCGGTTAATTAAAGGGAAAAATTAT3697                          SerAsnTyrSerAspCysLysValArgLeuIleLysGlyLysAsnTyr                              121012151220                                                                  TATTTCGCAGCACGCAATAATATGGCATTAGGGAAATACGTTGATTTA3745                          TyrPheAlaAlaArgAsnAsnMetAlaLeuGlyLysTyrValAspLeu                              1225123012351240                                                              GGTTTAGGTATGAGGTATGACGTATCTCGTACAAAAGCTAATGAATCA3793                          GlyLeuGlyMetArgTyrAspValSerArgThrLysAlaAsnGluSer                              124512501255                                                                  ACTATTAGTGTTGGTAAATTTAAAAATTTCTCTTGGAATACTGGTATT3841                          ThrIleSerValGlyLysPheLysAsnPheSerTrpAsnThrGlyIle                              126012651270                                                                  GTCATAAAACCAACGGAATGGCTTGATCTTTCTTATCGCCTTTCTACT3889                          ValIleLysProThrGluTrpLeuAspLeuSerTyrArgLeuSerThr                              127512801285                                                                  GGATTTAGAAATCCTAGTTTTGCTGAAATGTATGGTTGGCGGTATGGT3937                          GlyPheArgAsnProSerPheAlaGluMetTyrGlyTrpArgTyrGly                              129012951300                                                                  GGCAAGGATACCGATGTTTATATAGGTAAATTTAAGCCTGAAACATCT3985                          GlyLysAspThrAspValTyrIleGlyLysPheLysProGluThrSer                              1305131013151320                                                              CGTAACCAAGAGTTTGGTCTCGCTCTAAAAGGGGATTTTGGTAATATT4033                          ArgAsnGlnGluPheGlyLeuAlaLeuLysGlyAspPheGlyAsnIle                              132513301335                                                                  GAGATCAGTCATTTTAGTAATGCTTATCGAAATCTTATCGCCTTTGCT4081                          GluIleSerHisPheSerAsnAlaTyrArgAsnLeuIleAlaPheAla                              134013451350                                                                  GAAGAACTTAGTAAAAATGGAACTACTGGAAAGGGCAATTATGGATAT4129                          GluGluLeuSerLysAsnGlyThrThrGlyLysGlyAsnTyrGlyTyr                              135513601365                                                                  CATAATGCACAAAATGCAAAATTAGTTGGCGTAAATATAACTGCGCAA4177                          HisAsnAlaGlnAsnAlaLysLeuValGlyValAsnIleThrAlaGln                              137013751380                                                                  TTAGATTTTAATGGTTTATGGAAACGTATTCCCTACGGTTGGTATGCA4225                          LeuAspPheAsnGlyLeuTrpLysArgIleProTyrGlyTrpTyrAla                              1385139013951400                                                              ACATTTGCTTATAACCGAGTAAAAGTTAAAGATCAAAAAATCAATGCT4273                          ThrPheAlaTyrAsnArgValLysValLysAspGlnLysIleAsnAla                              140514101415                                                                  GGTTTAGCTTCCGTAAGCAGTTATTTATTTGATGCCATTCAGCCCAGC4321                          GlyLeuAlaSerValSerSerTyrLeuPheAspAlaIleGlnProSer                              142014251430                                                                  CGTTATATCATTGGTTTAGGCTATGATCATCCAAGTAATACTTGGGGA4369                          ArgTyrIleIleGlyLeuGlyTyrAspHisProSerAsnThrTrpGly                              143514401445                                                                  ATTAAGACAATGTTTACTCAATCAAAAGCAAAATCTCAAAATGAATTG4417                          IleLysThrMetPheThrGlnSerLysAlaLysSerGlnAsnGluLeu                              145014551460                                                                  CTAGGAAAACGTGCATTGGGTAACAATTCAAGGAATGTAAAATCAACA4465                          LeuGlyLysArgAlaLeuGlyAsnAsnSerArgAsnValLysSerThr                              1465147014751480                                                              AGAAAACTTACTCGGGCATGGCATATCTTAGATGTATCGGGTTATTAC4513                          ArgLysLeuThrArgAlaTrpHisIleLeuAspValSerGlyTyrTyr                              148514901495                                                                  ATGGTGAATAGAAGTATTTTGTTCCGATTAGGAGTATATAATTTATTA4561                          MetValAsnArgSerIleLeuPheArgLeuGlyValTyrAsnLeuLeu                              150015051510                                                                  AACTATCGCTATGTCACTTGGGAAGCGGTGCGTCAAACAGCACAAGGT4609                          AsnTyrArgTyrValThrTrpGluAlaValArgGlnThrAlaGlnGly                              151515201525                                                                  GCGGTCAATCAACATCAAAATGTTGGTAACTATACTCGCTACGCAGCA4657                          AlaValAsnGlnHisGlnAsnValGlyAsnTyrThrArgTyrAlaAla                              153015351540                                                                  TCAGGACGAAACTATACCTTAACATTAGAAATGAAATTCTAA4699                                SerGlyArgAsnTyrThrLeuThrLeuGluMetLysPhe                                       154515501555                                                                  (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5033 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: join(169..2148, 2165..4900)                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       GCCCAAGCTACATTGGTTAATGATAAGCCTATAAATGATAAGAAAGAAATTTGTTTTACG60                CCATTTTTCATATTTTATCCATGAACTTAAAAAACTCTAACTTGACATTATTACAAAAAA120               AGATCAATAATGCGAATTATTATCAATTTTGTATGAGTATATAATTCTATGAAATCT177                  MetLysSer                                                                     GTACCTCTTATCTCTGGTGGACTTTCCTTTTTACTAAGTGCTTGTAGC225                           ValProLeuIleSerGlyGlyLeuSerPheLeuLeuSerAlaCysSer                              51015                                                                         GGAGGGGGGTCTTTTGATGTAGATAACGTCTCTAATACCCCCTCTTCT273                           GlyGlyGlySerPheAspValAspAsnValSerAsnThrProSerSer                              20253035                                                                      AAACCACGTTATCAAGACGATACCTCGAATCAAAGAAAAAAATCTAAT321                           LysProArgTyrGlnAspAspThrSerAsnGlnArgLysLysSerAsn                              404550                                                                        TTGAAAAAGTTGTTCATTCCTTCTTTAGGAGGAGGGATGAAATTGGTG369                           LeuLysLysLeuPheIleProSerLeuGlyGlyGlyMetLysLeuVal                              556065                                                                        GCTCAGAATCTTCGTGGTAATAAAGAACCTAGTTTCTTAAATGAAGAT417                           AlaGlnAsnLeuArgGlyAsnLysGluProSerPheLeuAsnGluAsp                              707580                                                                        GACTATATATCATATTTTTCCTCACTTTCTACGATTGAAAAGGATGTT465                           AspTyrIleSerTyrPheSerSerLeuSerThrIleGluLysAspVal                              859095                                                                        AAAGATAACAATAAAAACGGGGCGGACCTTATTGGCTCAATAGACGAG513                           LysAspAsnAsnLysAsnGlyAlaAspLeuIleGlySerIleAspGlu                              100105110115                                                                  CCTAGTACAACAAATCCACCCGAAAAGCATCATGGACAAAAATATGTA561                           ProSerThrThrAsnProProGluLysHisHisGlyGlnLysTyrVal                              120125130                                                                     TATTCAGGGCTTTATTATACTCCATCGTGGAGTTTAAACGATTCTAAA609                           TyrSerGlyLeuTyrTyrThrProSerTrpSerLeuAsnAspSerLys                              135140145                                                                     AACAAGTTTTATTTAGGTTACTATGGATATGCGTTTTATTATGGTAAT657                           AsnLysPheTyrLeuGlyTyrTyrGlyTyrAlaPheTyrTyrGlyAsn                              150155160                                                                     AAAACTGCAACAAACTTGCCAGTAAACGGTGTAGCTAAATACAAAGGA705                           LysThrAlaThrAsnLeuProValAsnGlyValAlaLysTyrLysGly                              165170175                                                                     ACTTGGGATTTCATCACTGCAACTAAAAATGGCAAACGTTATCCTTTG753                           ThrTrpAspPheIleThrAlaThrLysAsnGlyLysArgTyrProLeu                              180185190195                                                                  TTAAGTAATGGCAGTCACGCTTATTATCGACGTAGTGCAATTCCAGAA801                           LeuSerAsnGlySerHisAlaTyrTyrArgArgSerAlaIleProGlu                              200205210                                                                     GATATTGATTTAGAAAATGATTCAAAGAATGGTGATATAGGCTTAATA849                           AspIleAspLeuGluAsnAspSerLysAsnGlyAspIleGlyLeuIle                              215220225                                                                     AGTGAATTTAGTGCAGATTTTGGGACTAAAAAACTGACAGGACAACTG897                           SerGluPheSerAlaAspPheGlyThrLysLysLeuThrGlyGlnLeu                              230235240                                                                     TCTTACACCAAAAGAAAAACTAATAATCAACCATATGAAAAGAAAAAA945                           SerTyrThrLysArgLysThrAsnAsnGlnProTyrGluLysLysLys                              245250255                                                                     CTCTATGATATAGATGCCGATATTTATAGTAATAGATTCAGGGGTACA993                           LeuTyrAspIleAspAlaAspIleTyrSerAsnArgPheArgGlyThr                              260265270275                                                                  GTAAAGCCAACCGAAAAAGATTCTGAAGAACATCCCTTTACCAGCGAG1041                          ValLysProThrGluLysAspSerGluGluHisProPheThrSerGlu                              280285290                                                                     GGAACATTAGAAGGTGGTTTTTATGGGCCTAATGCTGAAGAACTAGGG1089                          GlyThrLeuGluGlyGlyPheTyrGlyProAsnAlaGluGluLeuGly                              295300305                                                                     GGGAAATTTTTAGCTACGGATAACCGAGTTTTTGGGGTATTTAGTGCC1137                          GlyLysPheLeuAlaThrAspAsnArgValPheGlyValPheSerAla                              310315320                                                                     AAAGAAACGGAAGAAACAAAAAAGGAAGCGTTATCCAAGGAAACCTTA1185                          LysGluThrGluGluThrLysLysGluAlaLeuSerLysGluThrLeu                              325330335                                                                     ATTGATGGCAAGCTAATTACTTTCTCTACTAAAAAAACCGATGCAAAA1233                          IleAspGlyLysLeuIleThrPheSerThrLysLysThrAspAlaLys                              340345350355                                                                  ACCAATGCAACAACCAGTACCGCAGCTAATACAACAACCGATACAACC1281                          ThrAsnAlaThrThrSerThrAlaAlaAsnThrThrThrAspThrThr                              360365370                                                                     GCCAATACAATAACCGATGAAAAAAACTTTAAGACGGAAGATATATCA1329                          AlaAsnThrIleThrAspGluLysAsnPheLysThrGluAspIleSer                              375380385                                                                     AGTTTTGGTGAAGCTGATTATCTGTTAATTGACAAATATCCTATTCCA1377                          SerPheGlyGluAlaAspTyrLeuLeuIleAspLysTyrProIlePro                              390395400                                                                     CTTTTACCTGATAAAAATACTAATGATTTCATAAGTAGTAAGCATCAT1425                          LeuLeuProAspLysAsnThrAsnAspPheIleSerSerLysHisHis                              405410415                                                                     ACTGTAGGAAATAAACGCTATAAAGTGGAAGCATGTTGCAGTAATCTA1473                          ThrValGlyAsnLysArgTyrLysValGluAlaCysCysSerAsnLeu                              420425430435                                                                  AGCTATGTGAAATTTGGTATGTATTATGAAGACCCACTTAAAGAAAAA1521                          SerTyrValLysPheGlyMetTyrTyrGluAspProLeuLysGluLys                              440445450                                                                     GAAACAGAAACAGAAACAGAAACAGAAAAAGACAAAGAAAAAGAAAAA1569                          GluThrGluThrGluThrGluThrGluLysAspLysGluLysGluLys                              455460465                                                                     GAAAAAGACAAAGACAAAGAAAAACAAACGGCGGCAACGACCAACACT1617                          GluLysAspLysAspLysGluLysGlnThrAlaAlaThrThrAsnThr                              470475480                                                                     TATTATCAATTCTTATTAGGTCACCGTACTCCCAAGGACGACATACCT1665                          TyrTyrGlnPheLeuLeuGlyHisArgThrProLysAspAspIlePro                              485490495                                                                     AAAACAGGAAGTGCAAAATATCATGGTAGTTGGTTTGGTTATATTACT1713                          LysThrGlySerAlaLysTyrHisGlySerTrpPheGlyTyrIleThr                              500505510515                                                                  GACGGTAAGACATCTTACTCCCCCAGTGGTGATAAGAAACGCGATAAA1761                          AspGlyLysThrSerTyrSerProSerGlyAspLysLysArgAspLys                              520525530                                                                     AATGCTGTCGCCGAGTTTAATGTTGATTTTGCCGAGAAAAAGCTAACA1809                          AsnAlaValAlaGluPheAsnValAspPheAlaGluLysLysLeuThr                              535540545                                                                     GGCGAATTAAAACGACACGATACTGGAAATCCCGTATTTAGTATTGAG1857                          GlyGluLeuLysArgHisAspThrGlyAsnProValPheSerIleGlu                              550555560                                                                     GCAAACTTTAATAATAGTAGTAATGCCTTCACTGGTACAGCAACCGCA1905                          AlaAsnPheAsnAsnSerSerAsnAlaPheThrGlyThrAlaThrAla                              565570575                                                                     ACAAATTTTGTAATAGATGGTAAAAATAGTCAAAATAAAAATACCCCA1953                          ThrAsnPheValIleAspGlyLysAsnSerGlnAsnLysAsnThrPro                              580585590595                                                                  ATTAATATTACAACTAAAGTAAACGGGGCATTTTATGGACCTAAGGCT2001                          IleAsnIleThrThrLysValAsnGlyAlaPheTyrGlyProLysAla                              600605610                                                                     TCTGAATTAGGCGGTTATTTCACTTATAACGGAAATTCTACAGCTACA2049                          SerGluLeuGlyGlyTyrPheThrTyrAsnGlyAsnSerThrAlaThr                              615620625                                                                     AATTCTGAAAGTTCCTCAACCGTATCTTCATCATCCAATTCAAAAAAT2097                          AsnSerGluSerSerSerThrValSerSerSerSerAsnSerLysAsn                              630635640                                                                     GCAAGAGCTGCAGTTGTCTTTGGTGCGAGACAACAAGTAGAAACAACC2145                          AlaArgAlaAlaValValPheGlyAlaArgGlnGlnValGluThrThr                              645650655                                                                     AAATAATGGAATACTAAAAATGACTAAAAAACCCTATTTTCGCCTAAGT2194                         LysMetThrLysLysProTyrPheArgLeuSer                                             660665670                                                                     ATTATTTCTTGTCTTTTAATTTCATGCTATGTAAAAGCAGAAACTCAA2242                          IleIleSerCysLeuLeuIleSerCysTyrValLysAlaGluThrGln                              675680685                                                                     AGTATAAAAGATACAAAAGAAGCTATATCATCTGAAGTGGACACTCAA2290                          SerIleLysAspThrLysGluAlaIleSerSerGluValAspThrGln                              690695700                                                                     AGTACAGAAGATTCAGAATTAGAAACTATCTCAGTCACTGCAGAAAAA2338                          SerThrGluAspSerGluLeuGluThrIleSerValThrAlaGluLys                              705710715                                                                     ATAAGAGATCGTAAAGATAATGAAGTAACTGGACTTGGCAAAATTATC2386                          IleArgAspArgLysAspAsnGluValThrGlyLeuGlyLysIleIle                              720725730                                                                     AAAACTAGTGAAAGTATCAGCCGAGAACAAGTATTAAATATTCGTGAT2434                          LysThrSerGluSerIleSerArgGluGlnValLeuAsnIleArgAsp                              735740745750                                                                  CTAACACGCTATGATCCAGGGATTTCAGTTGTAGAACAAGGTCGCGGT2482                          LeuThrArgTyrAspProGlyIleSerValValGluGlnGlyArgGly                              755760765                                                                     GCAAGTTCTGGATATTCTATTCGTGGTATGGACAGAAATAGAGTTGCT2530                          AlaSerSerGlyTyrSerIleArgGlyMetAspArgAsnArgValAla                              770775780                                                                     TTATTAGTAGATGGTTTACCTCAAACGCAATCTTATGTAGTGCAAAGC2578                          LeuLeuValAspGlyLeuProGlnThrGlnSerTyrValValGlnSer                              785790795                                                                     CCTTTAGTTGCTCGTTCAGGATATTCTGGCACTGGTGCAATTAATGAA2626                          ProLeuValAlaArgSerGlyTyrSerGlyThrGlyAlaIleAsnGlu                              800805810                                                                     ATTGAATATGAAAATGTAAAGGCCGTCGAAATAAGCAAGGGGGGGAGT2674                          IleGluTyrGluAsnValLysAlaValGluIleSerLysGlyGlySer                              815820825830                                                                  TCTTCTGAGTATGGTAATGGAGCACTAGCTGGTTCTGTAACATTTCAA2722                          SerSerGluTyrGlyAsnGlyAlaLeuAlaGlySerValThrPheGln                              835840845                                                                     AGCAAATCAGCAGCCGATATCTTAGAAGGAGACAAATCATGGGGAATT2770                          SerLysSerAlaAlaAspIleLeuGluGlyAspLysSerTrpGlyIle                              850855860                                                                     CAAACTAAAAATGCTTATTCAAGCAAAAATAAAGGCTTTACCCATTCT2818                          GlnThrLysAsnAlaTyrSerSerLysAsnLysGlyPheThrHisSer                              865870875                                                                     TTAGCTGTAGCAGGAAAACAAGGTGGATTTGAAGGGCTAGCCATTTAC2866                          LeuAlaValAlaGlyLysGlnGlyGlyPheGluGlyLeuAlaIleTyr                              880885890                                                                     ACTCAACGAAATTCAATTGAAACCCAAGTCCATAAAGATGCATTAAAA2914                          ThrGlnArgAsnSerIleGluThrGlnValHisLysAspAlaLeuLys                              895900905910                                                                  GGCGTACAAAGTTATGATCGATTAATCGCCACAACAGATAAATCTTCA2962                          GlyValGlnSerTyrAspArgLeuIleAlaThrThrAspLysSerSer                              915920925                                                                     GGATACTTTGTGATACAAGGTGAGTGTCCAAATGGTGATGACAAGTGT3010                          GlyTyrPheValIleGlnGlyGluCysProAsnGlyAspAspLysCys                              930935940                                                                     GCAGCCAAGCCACCTGCGACTTTATCCACCCAAAGCGAAACCGTAAGC3058                          AlaAlaLysProProAlaThrLeuSerThrGlnSerGluThrValSer                              945950955                                                                     GTTTCAGATTATACGGGGGCTAACCGTATCAAACCTAATCCAATGAAA3106                          ValSerAspTyrThrGlyAlaAsnArgIleLysProAsnProMetLys                              960965970                                                                     TATGAAAGCCAGTCTTGGTTTTTAAGAGGAGGGTATCATTTTTCTGAA3154                          TyrGluSerGlnSerTrpPheLeuArgGlyGlyTyrHisPheSerGlu                              975980985990                                                                  CAACATTATATTGGTGGTATTTTTGAATTCACACAACAAAAATTTGAT3202                          GlnHisTyrIleGlyGlyIlePheGluPheThrGlnGlnLysPheAsp                              99510001005                                                                   ATCCGTGATATGACATTTCCCGCTTATTTAAGCCCAACAGAAAGACGG3250                          IleArgAspMetThrPheProAlaTyrLeuSerProThrGluArgArg                              101010151020                                                                  GATGATAGTAGTCGTTCTTTTTATCCAATGCAAGATCATGGTGCATAT3298                          AspAspSerSerArgSerPheTyrProMetGlnAspHisGlyAlaTyr                              102510301035                                                                  CAACATATTGAGGATGGCAGAGGCGTTAAATATGCAAGTGGGCTTTAT3346                          GlnHisIleGluAspGlyArgGlyValLysTyrAlaSerGlyLeuTyr                              104010451050                                                                  TTCGATGAACACCATAGAAAACAGCGTGTAGGTATTGAATATATTTAC3394                          PheAspGluHisHisArgLysGlnArgValGlyIleGluTyrIleTyr                              1055106010651070                                                              GAAAATAAGAACAAAGCGGGCATCATTGACAAAGCAGTGTTAAGTGCT3442                          GluAsnLysAsnLysAlaGlyIleIleAspLysAlaValLeuSerAla                              107510801085                                                                  AATCAACAAAACATCATACTTGACAGTTATATGCGACATACGCATTGC3490                          AsnGlnGlnAsnIleIleLeuAspSerTyrMetArgHisThrHisCys                              109010951100                                                                  AGTCTTTATCCTAATCCAAGTAAGAATTGCCGCCCAACACTTGATAAA3538                          SerLeuTyrProAsnProSerLysAsnCysArgProThrLeuAspLys                              110511101115                                                                  CCTTATTCATACTATCGTTCTGATAGAAATGTTTATAAAGAAAAACAT3586                          ProTyrSerTyrTyrArgSerAspArgAsnValTyrLysGluLysHis                              112011251130                                                                  AATATGTTGCAATTGAATTTAGAGAAAAAAATTCAACAAAATTGGCTT3634                          AsnMetLeuGlnLeuAsnLeuGluLysLysIleGlnGlnAsnTrpLeu                              1135114011451150                                                              ACTCATCAAATTGTCTTCAATCTTGGTTTTGATGACTTTACTTCAGCG3682                          ThrHisGlnIleValPheAsnLeuGlyPheAspAspPheThrSerAla                              115511601165                                                                  CTTCAGCATAAAGATTATTTAACTCGACGTGTTATCGCTACGGCAGAT3730                          LeuGlnHisLysAspTyrLeuThrArgArgValIleAlaThrAlaAsp                              117011751180                                                                  AGTATTCCAAGGAAACCTGGTGAAACTGGTAAACCAAGAAATGGTTTG3778                          SerIleProArgLysProGlyGluThrGlyLysProArgAsnGlyLeu                              118511901195                                                                  CAATCACAACCTTACTTATACCCAAAACCAGAGCCATATTTTGCAGGA3826                          GlnSerGlnProTyrLeuTyrProLysProGluProTyrPheAlaGly                              120012051210                                                                  CAAGATCATTGTAATTATCAAGGTAGCTCCTCTAATTACAGAGACTGT3874                          GlnAspHisCysAsnTyrGlnGlySerSerSerAsnTyrArgAspCys                              1215122012251230                                                              AAAGTGCGGTTAATTAAAGGGAAAAATTATTATTTCGCAGCACGCAAT3922                          LysValArgLeuIleLysGlyLysAsnTyrTyrPheAlaAlaArgAsn                              123512401245                                                                  AATATGGCATTAGGGAAATACGTTGATTTAGGTTTAGGTATTCGGTAT3970                          AsnMetAlaLeuGlyLysTyrValAspLeuGlyLeuGlyIleArgTyr                              125012551260                                                                  GACGTATCTCGTACAAAAGCTAATGAATCAACTATTAGTGTTGGTAAA4018                          AspValSerArgThrLysAlaAsnGluSerThrIleSerValGlyLys                              126512701275                                                                  TTTAAAAATTTCTCTTGGAATACTGGTATTGTCATAAAACCAACGGAA4066                          PheLysAsnPheSerTrpAsnThrGlyIleValIleLysProThrGlu                              128012851290                                                                  TGGCTTGATCTTTCTTATCGCCTTTCTACTGGATTTAGAAATCCTAGT4114                          TrpLeuAspLeuSerTyrArgLeuSerThrGlyPheArgAsnProSer                              1295130013051310                                                              TTTTCTGAAATGTATGGTTGGCGGTATGGTGGCAAGAATGACGAGGTT4162                          PheSerGluMetTyrGlyTrpArgTyrGlyGlyLysAsnAspGluVal                              131513201325                                                                  TATGTAGGTAAATTTAAGCCTGAAACATCTCGTAACCAAGAGTTTGGT4210                          TyrValGlyLysPheLysProGluThrSerArgAsnGlnGluPheGly                              133013351340                                                                  CTCGCTCTAAAAGGGGATTTTGGTAATATTGAGATCAGTCATTTTAGT4258                          LeuAlaLeuLysGlyAspPheGlyAsnIleGluIleSerHisPheSer                              134513501355                                                                  AATGCTTATCGAAATCTTATCGCCTTTGCTGAAGAACTTAGTAAAAAT4306                          AsnAlaTyrArgAsnLeuIleAlaPheAlaGluGluLeuSerLysAsn                              136013651370                                                                  GGAACTGGAAAGGGCAATTATGGATATCATAATGCACAAAATGCAAAA4354                          GlyThrGlyLysGlyAsnTyrGlyTyrHisAsnAlaGlnAsnAlaLys                              1375138013851390                                                              TTAGTTGGCGTAAATATAACTGCACAATTAGATTTTAATGGTTTATGG4402                          LeuValGlyValAsnIleThrAlaGlnLeuAspPheAsnGlyLeuTrp                              139514001405                                                                  AAACGTATTCCCTACGGTTGGTATGCAACATTTGCTTATAACCAAGTA4450                          LysArgIleProTyrGlyTrpTyrAlaThrPheAlaTyrAsnGlnVal                              141014151420                                                                  AAAGTTAAAGATCAAAAAATCAATGCTGGTTTAGCCTCCGTAAGCAGT4498                          LysValLysAspGlnLysIleAsnAlaGlyLeuAlaSerValSerSer                              142514301435                                                                  TATTTATTTGATGCCATTCAGCCCAGCCGTTATATCATTGGTTTAGGC4546                          TyrLeuPheAspAlaIleGlnProSerArgTyrIleIleGlyLeuGly                              144014451450                                                                  TATGATCATCCAAGTAATACTTGGGGAATTAATACAATGTTTACTCAA4594                          TyrAspHisProSerAsnThrTrpGlyIleAsnThrMetPheThrGln                              1455146014651470                                                              TCAAAAGCAAAATCTCAAAATGAATTGCTAGGAAAACGTGCATTAGGT4642                          SerLysAlaLysSerGlnAsnGluLeuLeuGlyLysArgAlaLeuGly                              147514801485                                                                  AACAATTCAAGGGATGTAAAATCAACAAGAAAACTTACTCGGGCATGG4690                          AsnAsnSerArgAspValLysSerThrArgLysLeuThrArgAlaTrp                              149014951500                                                                  CATATCTTAGATGTATCGGGTTATTACATGGCGAATAAAAATATTATG4738                          HisIleLeuAspValSerGlyTyrTyrMetAlaAsnLysAsnIleMet                              150515101515                                                                  CTTCGATTAGGGATATATAATTTATTCAACTATCGCTATGTTACTTGG4786                          LeuArgLeuGlyIleTyrAsnLeuPheAsnTyrArgTyrValThrTrp                              152015251530                                                                  GAAGCGGTGCGTCAAACAGCACAAGGTGCGGTCAATCAACATCAAAAT4834                          GluAlaValArgGlnThrAlaGlnGlyAlaValAsnGlnHisGlnAsn                              1535154015451550                                                              GTTGGTAGCTATACTCGCTACGCAGCATCAGGACGAAACTATACCTTA4882                          ValGlySerTyrThrArgTyrAlaAlaSerGlyArgAsnTyrThrLeu                              155515601565                                                                  ACATTAGAAATGAAATTCTAAATTAAAATGCGCCAGATGGACTAGATA4930                          ThrLeuGluMetLysPhe                                                            1570                                                                          TGCTATATCTATACCTTACTGGCGCATCTTTTTCTGTTCTATAATCTGCTTAAGTGAAAA4990              ACCAAACTTGGATTTTTTACAAGATCTTTTCACACATTTATTG5033                               (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5009 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: join(121..2100, 2117..4852)                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       ATTTGTTTTACGCCATTTTTCATATTTTATCCATGAACTTAAAAAACTCTAACTTGACAT60                TATTACAAAAAAAGATCAATAATGCGAATTATTATCAATTTTGTATGAGTATATAATTCT120               ATGAAATCTGTACCTCTTATCTCTGGTGGACTTTCCTTTTTACTAAGT168                           MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        GCTTGTAGCGGAGGGGGGTCTTTTGATGTAGATAACGTCTCTAATACC216                           AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnThr                              202530                                                                        CCCTCTTCTAAACCACGTTATCAAGACGATACCTCGAATCAAAGAAAA264                           ProSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArgLys                              354045                                                                        AAATCTAATTTGAAAAAGTTGTTCATTCCTTCTTTAGGAGGAGGGATG312                           LysSerAsnLeuLysLysLeuPheIleProSerLeuGlyGlyGlyMet                              505560                                                                        AAATTGGTGGCTCAGAATCTTCGTGGTAATAAAGAACCTAGTTTCTTA360                           LysLeuValAlaGlnAsnLeuArgGlyAsnLysGluProSerPheLeu                              65707580                                                                      AATGAAGATGACTATATATCATATTTTTCCTCACTTTCTACGATTGAA408                           AsnGluAspAspTyrIleSerTyrPheSerSerLeuSerThrIleGlu                              859095                                                                        AAGGATGTTAAAGATAACAATAAAAACGGGGCGGACCTTATTGGCTCA456                           LysAspValLysAspAsnAsnLysAsnGlyAlaAspLeuIleGlySer                              100105110                                                                     ATAGACGAGCCTAGTACAACAAATCCACCCGAAAAGCATCATGGACAA504                           IleAspGluProSerThrThrAsnProProGluLysHisHisGlyGln                              115120125                                                                     AAATATGTATATTCAGGGCTTTATTATACTCCATCGTGGAGTTTAAAC552                           LysTyrValTyrSerGlyLeuTyrTyrThrProSerTrpSerLeuAsn                              130135140                                                                     GATTCTAAAAACAAGTTTTATTTAGGTTACTATGGATATGCGTTTTAT600                           AspSerLysAsnLysPheTyrLeuGlyTyrTyrGlyTyrAlaPheTyr                              145150155160                                                                  TATGGTAATAAAACTGCAACAAACTTGCCAGTAAACGGTGTAGCTAAA648                           TyrGlyAsnLysThrAlaThrAsnLeuProValAsnGlyValAlaLys                              165170175                                                                     TACAAAGGAACTTGGGATTTCATCACTGCAACTAAAAATGGCAAACGT696                           TyrLysGlyThrTrpAspPheIleThrAlaThrLysAsnGlyLysArg                              180185190                                                                     TATCCTTTGTTAAGTAATGGCAGTCACGCTTATTATCGACGTAGTGCA744                           TyrProLeuLeuSerAsnGlySerHisAlaTyrTyrArgArgSerAla                              195200205                                                                     ATTCCAGAAGATATTGATTTAGAAAATGATTCAAAGAATGGTGATATA792                           IleProGluAspIleAspLeuGluAsnAspSerLysAsnGlyAspIle                              210215220                                                                     GGCTTAATAAGTGAATTTAGTGCAGATTTTGGGACTAAAAAACTGACA840                           GlyLeuIleSerGluPheSerAlaAspPheGlyThrLysLysLeuThr                              225230235240                                                                  GGACAACTGTCTTACACCAAAAGAAAAACTAATAATCAACCATATGAA888                           GlyGlnLeuSerTyrThrLysArgLysThrAsnAsnGlnProTyrGlu                              245250255                                                                     AAGAAAAAACTCTATGATATAGATGCCGATATTTATAGTAATAGATTC936                           LysLysLysLeuTyrAspIleAspAlaAspIleTyrSerAsnArgPhe                              260265270                                                                     AGGGGTACAGTAAAGCCAACCGAAAAAGATTCTGAAGAACATCCCTTT984                           ArgGlyThrValLysProThrGluLysAspSerGluGluHisProPhe                              275280285                                                                     ACCAGCGAGGGAACATTAGAAGGTGGTTTTTATGGGCCTAATGCTGAA1032                          ThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsnAlaGlu                              290295300                                                                     GAACTAGGGGGGAAATTTTTAGCTACGGATAACCGAGTTTTTGGGGTA1080                          GluLeuGlyGlyLysPheLeuAlaThrAspAsnArgValPheGlyVal                              305310315320                                                                  TTTAGTGCCAAAGAAACGGAAGAAACAAAAAAGGAAGCGTTATCCAAG1128                          PheSerAlaLysGluThrGluGluThrLysLysGluAlaLeuSerLys                              325330335                                                                     GAAACCTTAATTGATGGCAAGCTAATTACTTTCTCTACTAAAAAAACC1176                          GluThrLeuIleAspGlyLysLeuIleThrPheSerThrLysLysThr                              340345350                                                                     GATGCAAAAACCAATGCAACAACCAGTACCGCAGCTAATACAACAACC1224                          AspAlaLysThrAsnAlaThrThrSerThrAlaAlaAsnThrThrThr                              355360365                                                                     GATACAACCGCCAATACAATAACCGATGAAAAAAACTTTAAGACGGAA1272                          AspThrThrAlaAsnThrIleThrAspGluLysAsnPheLysThrGlu                              370375380                                                                     GATATATCAAGTTTTGGTGAAGCTGATTATCTGTTAATTGACAAATAT1320                          AspIleSerSerPheGlyGluAlaAspTyrLeuLeuIleAspLysTyr                              385390395400                                                                  CCTATTCCACTTTTACCTGATAAAAATACTAATGATTTCATAAGTAGT1368                          ProIleProLeuLeuProAspLysAsnThrAsnAspPheIleSerSer                              405410415                                                                     AAGCATCATACTGTAGGAAATAAACGCTATAAAGTGGAAGCATGTTGC1416                          LysHisHisThrValGlyAsnLysArgTyrLysValGluAlaCysCys                              420425430                                                                     AGTAATCTAAGCTATGTGAAATTTGGTATGTATTATGAAGACCCACTT1464                          SerAsnLeuSerTyrValLysPheGlyMetTyrTyrGluAspProLeu                              435440445                                                                     AAAGAAAAAGAAACAGAAACAGAAACAGAAACAGAAAAAGACAAAGAA1512                          LysGluLysGluThrGluThrGluThrGluThrGluLysAspLysGlu                              450455460                                                                     AAAGAAAAAGAAAAAGACAAAGACAAAGAAAAACAAACGGCGGCAACG1560                          LysGluLysGluLysAspLysAspLysGluLysGlnThrAlaAlaThr                              465470475480                                                                  ACCAACACTTATTATCAATTCTTATTAGGTCACCGTACTCCCAAGGAC1608                          ThrAsnThrTyrTyrGlnPheLeuLeuGlyHisArgThrProLysAsp                              485490495                                                                     GACATACCTAAAACAGGAAGTGCAAAATATCATGGTAGTTGGTTTGGT1656                          AspIleProLysThrGlySerAlaLysTyrHisGlySerTrpPheGly                              500505510                                                                     TATATTACTGACGGTAAGACATCTTACTCCCCCAGTGGTGATAAGAAA1704                          TyrIleThrAspGlyLysThrSerTyrSerProSerGlyAspLysLys                              515520525                                                                     CGCGATAAAAATGCTGTCGCCGAGTTTAATGTTGATTTTGCCGAGAAA1752                          ArgAspLysAsnAlaValAlaGluPheAsnValAspPheAlaGluLys                              530535540                                                                     AAGCTAACAGGCGAATTAAAACGACACGATACTGGAAATCCCGTATTT1800                          LysLeuThrGlyGluLeuLysArgHisAspThrGlyAsnProValPhe                              545550555560                                                                  AGTATTGAGGCAAACTTTAATAATAGTAGTAATGCCTTCACTGGTACA1848                          SerIleGluAlaAsnPheAsnAsnSerSerAsnAlaPheThrGlyThr                              565570575                                                                     GCAACCGCAACAAATTTTGTAATAGATGGTAAAAATAGTCAAAATAAA1896                          AlaThrAlaThrAsnPheValIleAspGlyLysAsnSerGlnAsnLys                              580585590                                                                     AATACCCCAATTAATATTACAACTAAAGTAAACGGGGCATTTTATGGA1944                          AsnThrProIleAsnIleThrThrLysValAsnGlyAlaPheTyrGly                              595600605                                                                     CCTAAGGCTTCTGAATTAGGCGGTTATTTCACTTATAACGGAAATTCT1992                          ProLysAlaSerGluLeuGlyGlyTyrPheThrTyrAsnGlyAsnSer                              610615620                                                                     ACAGCTACAAATTCTGAAAGTTCCTCAACCGTATCTTCATCATCCAAT2040                          ThrAlaThrAsnSerGluSerSerSerThrValSerSerSerSerAsn                              625630635640                                                                  TCAAAAAATGCAAGAGCTGCAGTTGTCTTTGGTGCGAGACAACAAGTA2088                          SerLysAsnAlaArgAlaAlaValValPheGlyAlaArgGlnGlnVal                              645650655                                                                     GAAACAACCAAATAATGGAATACTAAAAATGACTAAAAAACCCTATTTT2137                         GluThrThrLysMetThrLysLysProTyrPhe                                             660665                                                                        CGCCTAAGTATTATTTCTTGTCTTTTAATTTCATGCTATGTAAAAGCA2185                          ArgLeuSerIleIleSerCysLeuLeuIleSerCysTyrValLysAla                              670675680                                                                     GAAACTCAAAGTATAAAAGATACAAAAGAAGCTATATCATCTGAAGTG2233                          GluThrGlnSerIleLysAspThrLysGluAlaIleSerSerGluVal                              685690695                                                                     GACACTCAAAGTACAGAAGATTCAGAATTAGAAACTATCTCAGTCACT2281                          AspThrGlnSerThrGluAspSerGluLeuGluThrIleSerValThr                              700705710715                                                                  GCAGAAAAAATAAGAGATCGTAAAGATAATGAAGTAACTGGACTTGGC2329                          AlaGluLysIleArgAspArgLysAspAsnGluValThrGlyLeuGly                              720725730                                                                     AAAATTATCAAAACTAGTGAAAGTATCAGCCGAGAACAAGTATTAAAT2377                          LysIleIleLysThrSerGluSerIleSerArgGluGlnValLeuAsn                              735740745                                                                     ATTCGTGATCTAACACGCTATGATCCAGGGATTTCAGTTGTAGAACAA2425                          IleArgAspLeuThrArgTyrAspProGlyIleSerValValGluGln                              750755760                                                                     GGTCGCGGTGCAAGTTCTGGATATTCTATTCGTGGTATGGACAGAAAT2473                          GlyArgGlyAlaSerSerGlyTyrSerIleArgGlyMetAspArgAsn                              765770775                                                                     AGAGTTGCTTTATTAGTAGATGGTTTACCTCAAACGCAATCTTATGTA2521                          ArgValAlaLeuLeuValAspGlyLeuProGlnThrGlnSerTyrVal                              780785790795                                                                  GTGCAAAGCCCTTTAGTTGCTCGTTCAGGATATTCTGGCACTGGTGCA2569                          ValGlnSerProLeuValAlaArgSerGlyTyrSerGlyThrGlyAla                              800805810                                                                     ATTAATGAAATTGAATATGAAAATGTAAAGGCCGTCGAAATAAGCAAG2617                          IleAsnGluIleGluTyrGluAsnValLysAlaValGluIleSerLys                              815820825                                                                     GGGGGGAGTTCTTCTGAGTATGGTAATGGAGCACTAGCTGGTTCTGTA2665                          GlyGlySerSerSerGluTyrGlyAsnGlyAlaLeuAlaGlySerVal                              830835840                                                                     ACATTTCAAAGCAAATCAGCAGCCGATATCTTAGAAGGAGACAAATCA2713                          ThrPheGlnSerLysSerAlaAlaAspIleLeuGluGlyAspLysSer                              845850855                                                                     TGGGGAATTCAAACTAAAAATGCTTATTCAAGCAAAAATAAAGGCTTT2761                          TrpGlyIleGlnThrLysAsnAlaTyrSerSerLysAsnLysGlyPhe                              860865870875                                                                  ACCCATTCTTTAGCTGTAGCAGGAAAACAAGGTGGATTTGAAGGGCTA2809                          ThrHisSerLeuAlaValAlaGlyLysGlnGlyGlyPheGluGlyLeu                              880885890                                                                     GCCATTTACACTCAACGAAATTCAATTGAAACCCAAGTCCATAAAGAT2857                          AlaIleTyrThrGlnArgAsnSerIleGluThrGlnValHisLysAsp                              895900905                                                                     GCATTAAAAGGCGTACAAAGTTATGATCGATTAATCGCCACAACAGAT2905                          AlaLeuLysGlyValGlnSerTyrAspArgLeuIleAlaThrThrAsp                              910915920                                                                     AAATCTTCAGGATACTTTGTGATACAAGGTGAGTGTCCAAATGGTGAT2953                          LysSerSerGlyTyrPheValIleGlnGlyGluCysProAsnGlyAsp                              925930935                                                                     GACAAGTGTGCAGCCAAGCCACCTGCGACTTTATCCACCCAAAGCGAA3001                          AspLysCysAlaAlaLysProProAlaThrLeuSerThrGlnSerGlu                              940945950955                                                                  ACCGTAAGCGTTTCAGATTATACGGGGGCTAACCGTATCAAACCTAAT3049                          ThrValSerValSerAspTyrThrGlyAlaAsnArgIleLysProAsn                              960965970                                                                     CCAATGAAATATGAAAGCCAGTCTTGGTTTTTAAGAGGAGGGTATCAT3097                          ProMetLysTyrGluSerGlnSerTrpPheLeuArgGlyGlyTyrHis                              975980985                                                                     TTTTCTGAACAACATTATATTGGTGGTATTTTTGAATTCACACAACAA3145                          PheSerGluGlnHisTyrIleGlyGlyIlePheGluPheThrGlnGln                              9909951000                                                                    AAATTTGATATCCGTGATATGACATTTCCCGCTTATTTAAGCCCAACA3193                          LysPheAspIleArgAspMetThrPheProAlaTyrLeuSerProThr                              100510101015                                                                  GAAAGACGGGATGATAGTAGTCGTTCTTTTTATCCAATGCAAGATCAT3241                          GluArgArgAspAspSerSerArgSerPheTyrProMetGlnAspHis                              1020102510301035                                                              GGTGCATATCAACATATTGAGGATGGCAGAGGCGTTAAATATGCAAGT3289                          GlyAlaTyrGlnHisIleGluAspGlyArgGlyValLysTyrAlaSer                              104010451050                                                                  GGGCTTTATTTCGATGAACACCATAGAAAACAGCGTGTAGGTATTGAA3337                          GlyLeuTyrPheAspGluHisHisArgLysGlnArgValGlyIleGlu                              105510601065                                                                  TATATTTACGAAAATAAGAACAAAGCGGGCATCATTGACAAAGCAGTG3385                          TyrIleTyrGluAsnLysAsnLysAlaGlyIleIleAspLysAlaVal                              107010751080                                                                  TTAAGTGCTAATCAACAAAACATCATACTTGACAGTTATATGCGACAT3433                          LeuSerAlaAsnGlnGlnAsnIleIleLeuAspSerTyrMetArgHis                              108510901095                                                                  ACGCATTGCAGTCTTTATCCTAATCCAAGTAAGAATTGCCGCCCAACA3481                          ThrHisCysSerLeuTyrProAsnProSerLysAsnCysArgProThr                              1100110511101115                                                              CTTGATAAACCTTATTCATACTATCGTTCTGATAGAAATGTTTATAAA3529                          LeuAspLysProTyrSerTyrTyrArgSerAspArgAsnValTyrLys                              112011251130                                                                  GAAAAACATAATATGTTGCAATTGAATTTAGAGAAAAAAATTCAACAA3577                          GluLysHisAsnMetLeuGlnLeuAsnLeuGluLysLysIleGlnGln                              113511401145                                                                  AATTGGCTTACTCATCAAATTGTCTTCAATCTTGGTTTTGATGACTTT3625                          AsnTrpLeuThrHisGlnIleValPheAsnLeuGlyPheAspAspPhe                              115011551160                                                                  ACTTCAGCGCTTCAGCATAAAGATTATTTAACTCGACGTGTTATCGCT3673                          ThrSerAlaLeuGlnHisLysAspTyrLeuThrArgArgValIleAla                              116511701175                                                                  ACGGCAGATAGTATTCCAAGGAAACCTGGTGAAACTGGTAAACCAAGA3721                          ThrAlaAspSerIleProArgLysProGlyGluThrGlyLysProArg                              1180118511901195                                                              AATGGTTTGCAATCACAACCTTACTTATACCCAAAACCAGAGCCATAT3769                          AsnGlyLeuGlnSerGlnProTyrLeuTyrProLysProGluProTyr                              120012051210                                                                  TTTGCAGGACAAGATCATTGTAATTATCAAGGTAGCTCCTCTAATTAC3817                          PheAlaGlyGlnAspHisCysAsnTyrGlnGlySerSerSerAsnTyr                              121512201225                                                                  AGAGACTGTAAAGTGCGGTTAATTAAAGGGAAAAATTATTATTTCGCA3865                          ArgAspCysLysValArgLeuIleLysGlyLysAsnTyrTyrPheAla                              123012351240                                                                  GCACGCAATAATATGGCATTAGGGAAATACGTTGATTTAGGTTTAGGT3913                          AlaArgAsnAsnMetAlaLeuGlyLysTyrValAspLeuGlyLeuGly                              124512501255                                                                  ATTCGGTATGACGTATCTCGTACAAAAGCTAATGAATCAACTATTAGT3961                          IleArgTyrAspValSerArgThrLysAlaAsnGluSerThrIleSer                              1260126512701275                                                              GTTGGTAAATTTAAAAATTTCTCTTGGAATACTGGTATTGTCATAAAA4009                          ValGlyLysPheLysAsnPheSerTrpAsnThrGlyIleValIleLys                              128012851290                                                                  CCAACGGAATGGCTTGATCTTTCTTATCGCCTTTCTACTGGATTTAGA4057                          ProThrGluTrpLeuAspLeuSerTyrArgLeuSerThrGlyPheArg                              129513001305                                                                  AATCCTAGTTTTTCTGAAATGTATGGTTGGCGGTATGGTGGCAAGAAT4105                          AsnProSerPheSerGluMetTyrGlyTrpArgTyrGlyGlyLysAsn                              131013151320                                                                  GACGAGGTTTATGTAGGTAAATTTAAGCCTGAAACATCTCGTAACCAA4153                          AspGluValTyrValGlyLysPheLysProGluThrSerArgAsnGln                              132513301335                                                                  GAGTTTGGTCTCGCTCTAAAAGGGGATTTTGGTAATATTGAGATCAGT4201                          GluPheGlyLeuAlaLeuLysGlyAspPheGlyAsnIleGluIleSer                              1340134513501355                                                              CATTTTAGTAATGCTTATCGAAATCTTATCGCCTTTGCTGAAGAACTT4249                          HisPheSerAsnAlaTyrArgAsnLeuIleAlaPheAlaGluGluLeu                              136013651370                                                                  AGTAAAAATGGAACTGGAAAGGGCAATTATGGATATCATAATGCACAA4297                          SerLysAsnGlyThrGlyLysGlyAsnTyrGlyTyrHisAsnAlaGln                              137513801385                                                                  AATGCAAAATTAGTTGGCGTAAATATAACTGCACAATTAGATTTTAAT4345                          AsnAlaLysLeuValGlyValAsnIleThrAlaGlnLeuAspPheAsn                              139013951400                                                                  GGTTTATGGAAACGTATTCCCTACGGTTGGTATGCAACATTTGCTTAT4393                          GlyLeuTrpLysArgIleProTyrGlyTrpTyrAlaThrPheAlaTyr                              140514101415                                                                  AACCAAGTAAAAGTTAAAGATCAAAAAATCAATGCTGGTTTAGCCTCC4441                          AsnGlnValLysValLysAspGlnLysIleAsnAlaGlyLeuAlaSer                              1420142514301435                                                              GTAAGCAGTTATTTATTTGATGCCATTCAGCCCAGCCGTTATATCATT4489                          ValSerSerTyrLeuPheAspAlaIleGlnProSerArgTyrIleIle                              144014451450                                                                  GGTTTAGGCTATGATCATCCAAGTAATACTTGGGGAATTAATACAATG4537                          GlyLeuGlyTyrAspHisProSerAsnThrTrpGlyIleAsnThrMet                              145514601465                                                                  TTTACTCAATCAAAAGCAAAATCTCAAAATGAATTGCTAGGAAAACGT4585                          PheThrGlnSerLysAlaLysSerGlnAsnGluLeuLeuGlyLysArg                              147014751480                                                                  GCATTAGGTAACAATTCAAGGGATGTAAAATCAACAAGAAAACTTACT4633                          AlaLeuGlyAsnAsnSerArgAspValLysSerThrArgLysLeuThr                              148514901495                                                                  CGGGCATGGCATATCTTAGATGTATCGGGTTATTACATGGCGAATAAA4681                          ArgAlaTrpHisIleLeuAspValSerGlyTyrTyrMetAlaAsnLys                              1500150515101515                                                              AATATTATGCTTCGATTAGGGATATATAATTTATTCAACTATCGCTAT4729                          AsnIleMetLeuArgLeuGlyIleTyrAsnLeuPheAsnTyrArgTyr                              152015251530                                                                  GTTACTTGGGAAGCGGTGCGTCAAACAGCACAAGGTGCGGTCAATCAA4777                          ValThrTrpGluAlaValArgGlnThrAlaGlnGlyAlaValAsnGln                              153515401545                                                                  CATCAAAATGTTGGTAGCTATACTCGCTACGCAGCATCAGGACGAAAC4825                          HisGlnAsnValGlySerTyrThrArgTyrAlaAlaSerGlyArgAsn                              155015551560                                                                  TATACCTTAACATTAGAAATGAAATTCTAAATTAAAATGCGCCAGAT4872                           TyrThrLeuThrLeuGluMetLysPhe                                                   15651570                                                                      GGACTAGATATGCTATATCTATACCTTACTGGCGCATCTTTTTCTGTTCTATAATCTGCT4932              TAAGTGAAAAACCAAACTTGGATTTTTTACAAGATCTTTTCACACATTTATTGTAAAATC4992              TCCGACAATTTTGACCG5009                                                         (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5099 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: double                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: join(160..2121, 2152..4890)                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                       AAAATTCGGTAATGATAACCCTATAAATGATAAGAGAGAAAGTTGTTTTACGCCATTTTT60                CATATTTTATCCATGAACTTAAAAAATTCTAAGTTGACATTATTACAAAAAAAGAACAAT120               AATGCGAATTATTATCAATTTTGTATAAGTATTAATTCTATGAAATCTGTACCT174                     MetLysSerValPro                                                               15                                                                            CTTATCACTGGTGGACTTTCCTTTTTACTAAGCGCTTGTAGCGGGGGA222                           LeuIleThrGlyGlyLeuSerPheLeuLeuSerAlaCysSerGlyGly                              101520                                                                        GGTGGTTCTTTTGATGTAGATGACGTCTCTAATCCCTCCTCTTCTAAA270                           GlyGlySerPheAspValAspAspValSerAsnProSerSerSerLys                              253035                                                                        CCACGTTATCAAGACGATACCTCGAATCAAAGAACAAAATCTGATTTG318                           ProArgTyrGlnAspAspThrSerAsnGlnArgThrLysSerAspLeu                              404550                                                                        GAAAAGTTGTTCATTCCTTCTTTAGGGGGAGGGATGAAGTTAGTGGCT366                           GluLysLeuPheIleProSerLeuGlyGlyGlyMetLysLeuValAla                              556065                                                                        CAAAATTTTATTGGTGCTAGAGAACCTAGTTTCTTAAATGAAGATGGC414                           GlnAsnPheIleGlyAlaArgGluProSerPheLeuAsnGluAspGly                              70758085                                                                      TATATGATATTTTCCTCACTTTCTACGATTGAAGAGGATGTTGAAAAA462                           TyrMetIlePheSerSerLeuSerThrIleGluGluAspValGluLys                              9095100                                                                       GTTAAAAATAACAATAAAAACGGGGGGAGGCTTATTGGCTCAATTGAG510                           ValLysAsnAsnAsnLysAsnGlyGlyArgLeuIleGlySerIleGlu                              105110115                                                                     GAACCTAATGGAACATCACAAAATTCTAATTCACAAGAATACGTTTAT558                           GluProAsnGlyThrSerGlnAsnSerAsnSerGlnGluTyrValTyr                              120125130                                                                     TCTGGTTTGTATTATATCGATAGTTGGCGTGATTATAAGAAGGAAGAG606                           SerGlyLeuTyrTyrIleAspSerTrpArgAspTyrLysLysGluGlu                              135140145                                                                     CAAAAAGCTTATACTGGCTATTATGGTTATGCATTTTATTATGGTAAT654                           GlnLysAlaTyrThrGlyTyrTyrGlyTyrAlaPheTyrTyrGlyAsn                              150155160165                                                                  GAAACTGCAAAAAACTTGCCAGTAAAAGGTGTAGCTAAATACAAAGGA702                           GluThrAlaLysAsnLeuProValLysGlyValAlaLysTyrLysGly                              170175180                                                                     ACGTGGAACTTCATCACTGCAACTGAAAATGGCAAACGTTATTCTTTG750                           ThrTrpAsnPheIleThrAlaThrGluAsnGlyLysArgTyrSerLeu                              185190195                                                                     TTCAGTAATTCTATCGGTCAAGCTTATTCCAGACGCAGCGCTATTTCA798                           PheSerAsnSerIleGlyGlnAlaTyrSerArgArgSerAlaIleSer                              200205210                                                                     GAAGATATCTATAATTTAGAAAACGGTGACGCGGGCTTAATAAGTGAA846                           GluAspIleTyrAsnLeuGluAsnGlyAspAlaGlyLeuIleSerGlu                              215220225                                                                     TTTAGTGTAGATTTTGGTAAGAAAGAGCTCACTGGAGAACTTTATTAT894                           PheSerValAspPheGlyLysLysGluLeuThrGlyGluLeuTyrTyr                              230235240245                                                                  AATGAAAGGAAAACAAGTGTTAATGAATCACAAAATACAACACATAAA942                           AsnGluArgLysThrSerValAsnGluSerGlnAsnThrThrHisLys                              250255260                                                                     CTCTACACTCTAGAAGCTAAAGTGTATAGCAACCGATTCAGAGGTAAA990                           LeuTyrThrLeuGluAlaLysValTyrSerAsnArgPheArgGlyLys                              265270275                                                                     GTAAAGCCAACCAAAACAAAGTCTGAAGATCATCCCTTTACCAGCGAG1038                          ValLysProThrLysThrLysSerGluAspHisProPheThrSerGlu                              280285290                                                                     GGAACATTAGAAGGTGGTTTTTATGGGCCTAATGCTGAAGAACTAGGG1086                          GlyThrLeuGluGlyGlyPheTyrGlyProAsnAlaGluGluLeuGly                              295300305                                                                     GGAAAGTTTTTAGCTAACGACGAAAAAGTTTTTGGGGTATTTAGTGCC1134                          GlyLysPheLeuAlaAsnAspGluLysValPheGlyValPheSerAla                              310315320325                                                                  AAAGAAGACCCACAAAACCCAGAAAACCAAAAATTATCCACAGAAACC1182                          LysGluAspProGlnAsnProGluAsnGlnLysLeuSerThrGluThr                              330335340                                                                     TTAATTGATGGCAAGCTAATTACTTTTAAAAGAACTGATGCAACAACC1230                          LeuIleAspGlyLysLeuIleThrPheLysArgThrAspAlaThrThr                              345350355                                                                     AATGCAACAACCGATGCAAAAACCAGTGCAACAACCGATGCAACCAGT1278                          AsnAlaThrThrAspAlaLysThrSerAlaThrThrAspAlaThrSer                              360365370                                                                     ACAACAGCCAATAAAAAAACCGATGCAGAAAACTTTAAGACGGAAGAT1326                          ThrThrAlaAsnLysLysThrAspAlaGluAsnPheLysThrGluAsp                              375380385                                                                     ATACCAAGTTTTGGTGAAGCTGATTACCTTTTAATTGGCAATCAGCCT1374                          IleProSerPheGlyGluAlaAspTyrLeuLeuIleGlyAsnGlnPro                              390395400405                                                                  ATTCCTCTTTTACCTGAAAAAAATACTGATGATTTCATAAGTAGTAAG1422                          IleProLeuLeuProGluLysAsnThrAspAspPheIleSerSerLys                              410415420                                                                     CACCATACGGTAGGAGGTAAAACCTATAAAGTAGAAGCATGTTGCAAG1470                          HisHisThrValGlyGlyLysThrTyrLysValGluAlaCysCysLys                              425430435                                                                     AATCTAAGCTATGTGAAATTTGGTATGTATTATGAGGATAAAGATAAG1518                          AsnLeuSerTyrValLysPheGlyMetTyrTyrGluAspLysAspLys                              440445450                                                                     GACAACAAAAATGAAACAGACAAAGAAAAAGGCAAAGAAAAACCAACG1566                          AspAsnLysAsnGluThrAspLysGluLysGlyLysGluLysProThr                              455460465                                                                     ACGACAACATCTATCAACACTTATTATCAATTCTTATTAGGTCTCCGT1614                          ThrThrThrSerIleAsnThrTyrTyrGlnPheLeuLeuGlyLeuArg                              470475480485                                                                  ACTCCCAAGGACGAAATACCTAAAGAAGGAAGTGCAAAATATCATGGT1662                          ThrProLysAspGluIleProLysGluGlySerAlaLysTyrHisGly                              490495500                                                                     AATTGGTTTGGTTATATTAGTGATGGCGAGACATCTTACTCCGCCAGT1710                          AsnTrpPheGlyTyrIleSerAspGlyGluThrSerTyrSerAlaSer                              505510515                                                                     GGTGATAAGGAACGCAGTAAAAATGCTGTCGCCGAGTTTGATGTAAGT1758                          GlyAspLysGluArgSerLysAsnAlaValAlaGluPheAspValSer                              520525530                                                                     TTTGCCAATAAAACATTAACAGGCGAATTAAAACGACACGATAATGGA1806                          PheAlaAsnLysThrLeuThrGlyGluLeuLysArgHisAspAsnGly                              535540545                                                                     AATACCGTATTTAAAATTAATGCAGAATTAAATGGTAGTAATGACTTC1854                          AsnThrValPheLysIleAsnAlaGluLeuAsnGlySerAsnAspPhe                              550555560565                                                                  ACTGGTACAGCAACCGCAACAAATTTTGTAATAGATGGTAACAATAGT1902                          ThrGlyThrAlaThrAlaThrAsnPheValIleAspGlyAsnAsnSer                              570575580                                                                     CAAACTTCAAATGCCAAAATTAATATTACAACTAAAGTAAATGGGGCA1950                          GlnThrSerAsnAlaLysIleAsnIleThrThrLysValAsnGlyAla                              585590595                                                                     TTTTATGGACCTAAGGCTTCTGAATTAGGAGGGTATTTCACCTATAAC1998                          PheTyrGlyProLysAlaSerGluLeuGlyGlyTyrPheThrTyrAsn                              600605610                                                                     GGAAAAAATCCTACAGCTACAAATTCTGAAAGTTCCTCAACCGTACCT2046                          GlyLysAsnProThrAlaThrAsnSerGluSerSerSerThrValPro                              615620625                                                                     TCACCACCCAATTCACCAAATGCAAGCGCTGCAGTTGTCTTTGGTGCT2094                          SerProProAsnSerProAsnAlaSerAlaAlaValValPheGlyAla                              630635640645                                                                  AAAAAACAAGTAGAAACAACCAACAAGTAAAAACAACCAAGTAATGG2141                           LysLysGlnValGluThrThrAsnLys                                                   650                                                                           AATACTAAAAATGACTAAAAAACCCTATTTTCGCCTAAGTATTATTTCT2190                         MetThrLysLysProTyrPheArgLeuSerIleIleSer                                       655660665                                                                     TGTCTTTTAATTTCATGCTATGTAAAAGCAGAAACTCAAAGTATAAAA2238                          CysLeuLeuIleSerCysTyrValLysAlaGluThrGlnSerIleLys                              670675680                                                                     GATACAAAAGAAGCTATATCATCTGAAGTGGACACTCAAAGTACAGAA2286                          AspThrLysGluAlaIleSerSerGluValAspThrGlnSerThrGlu                              685690695                                                                     GATTCAGAATTAGAAACTATCTCAGTCACTGCAGAAAAAATAAGAGAT2334                          AspSerGluLeuGluThrIleSerValThrAlaGluLysIleArgAsp                              700705710715                                                                  CGTAAAGATAATGAAGTAACTGGACTTGGCAAAATTATCAAAACTAGT2382                          ArgLysAspAsnGluValThrGlyLeuGlyLysIleIleLysThrSer                              720725730                                                                     GAAAGTATCAGCCGAGAACAAGTATTAAATATTCGTGATCTAACACGC2430                          GluSerIleSerArgGluGlnValLeuAsnIleArgAspLeuThrArg                              735740745                                                                     TATGATCCAGGCATTTCAGTTGTAGAACAAGGCCGTGGTGCAAGTTCT2478                          TyrAspProGlyIleSerValValGluGlnGlyArgGlyAlaSerSer                              750755760                                                                     GGATATTCTATTCGTGGTATGGACAGAAATAGAGTTGCTTTATTAGTA2526                          GlyTyrSerIleArgGlyMetAspArgAsnArgValAlaLeuLeuVal                              765770775                                                                     GATGGTTTACCTCAAACGCAATCTTATGTAGTGCAAAGCCCTTTAGTT2574                          AspGlyLeuProGlnThrGlnSerTyrValValGlnSerProLeuVal                              780785790795                                                                  GCTCGTTCAGGATATTCTGGCACTGGTGCAATTAATGAAATTGAATAT2622                          AlaArgSerGlyTyrSerGlyThrGlyAlaIleAsnGluIleGluTyr                              800805810                                                                     GAAAATGTAAAGGCCGTCGAAATAAGCAAGGGGGGGAGTTCTTCTGAG2670                          GluAsnValLysAlaValGluIleSerLysGlyGlySerSerSerGlu                              815820825                                                                     TATGGTAATGGAGCACTAGCTGGTTCTGTAACATTTCAAAGCAAATCA2718                          TyrGlyAsnGlyAlaLeuAlaGlySerValThrPheGlnSerLysSer                              830835840                                                                     GCAGCCGATATCTTAGAAGGAGACAAATCATGGGGAATTCAAACTAAA2766                          AlaAlaAspIleLeuGluGlyAspLysSerTrpGlyIleGlnThrLys                              845850855                                                                     AATGCTTATTCAAGCAAAAATAAAGGCTTTACCCATTCTTTAGCTGTA2814                          AsnAlaTyrSerSerLysAsnLysGlyPheThrHisSerLeuAlaVal                              860865870875                                                                  GCTGGAAAACAAGGGGGATTTGACGGGGTCGCCATTTATACTCAACGA2862                          AlaGlyLysGlnGlyGlyPheAspGlyValAlaIleTyrThrGlnArg                              880885890                                                                     AATTCAATTGAAACCCAAGTCCATAAAGATGCATTAAAAGGCGTACAA2910                          AsnSerIleGluThrGlnValHisLysAspAlaLeuLysGlyValGln                              895900905                                                                     AGTTATCATCGATTAATCGCCAAACCAGAGGATCAATCTGCATACTTT2958                          SerTyrHisArgLeuIleAlaLysProGluAspGlnSerAlaTyrPhe                              910915920                                                                     GTGATGCAAGATGAGTGTCCAAAGCCAGATGATTATAACAGTTGTTTA3006                          ValMetGlnAspGluCysProLysProAspAspTyrAsnSerCysLeu                              925930935                                                                     CCTTTCGCCAAACGACCTGCGATTTTATCCTCCCAAAGAGAAACCGTA3054                          ProPheAlaLysArgProAlaIleLeuSerSerGlnArgGluThrVal                              940945950955                                                                  AGCGTTTCAGATTATACGGGGGCTAACCGTATCAAACCTAATCCAATG3102                          SerValSerAspTyrThrGlyAlaAsnArgIleLysProAsnProMet                              960965970                                                                     AAATATGAAAGCCAGTCTTGGTTTTTAAGAGGAGGGTATCATTTTTCT3150                          LysTyrGluSerGlnSerTrpPheLeuArgGlyGlyTyrHisPheSer                              975980985                                                                     GAACAACATTATATTGGTGGTATTTTTGAATTCACACAACAAAAATTT3198                          GluGlnHisTyrIleGlyGlyIlePheGluPheThrGlnGlnLysPhe                              9909951000                                                                    GATATCCGTGATATGACATTTCCCGCTTATTTAAGATCAACAGAAAAA3246                          AspIleArgAspMetThrPheProAlaTyrLeuArgSerThrGluLys                              100510101015                                                                  CGGGATGATAGCAGTGGCTCTTTTTATCCAAAGCAAGATTATGGTGCA3294                          ArgAspAspSerSerGlySerPheTyrProLysGlnAspTyrGlyAla                              1020102510301035                                                              TATCAACGTATTGAGGATGGCCGAGGCGTTAACTATGCAAGTGGGCTT3342                          TyrGlnArgIleGluAspGlyArgGlyValAsnTyrAlaSerGlyLeu                              104010451050                                                                  TATTTCGATGAACACCATAGAAAACAGCGTGTAGGTATTGAATATATT3390                          TyrPheAspGluHisHisArgLysGlnArgValGlyIleGluTyrIle                              105510601065                                                                  TACGAAAATAAGAACAAAGCGGGCATCATTGACAAAGCAGTGTTAAGT3438                          TyrGluAsnLysAsnLysAlaGlyIleIleAspLysAlaValLeuSer                              107010751080                                                                  GCTAATCAACAAAACATCATACTTGACAGTTATATGCAACATACGCAT3486                          AlaAsnGlnGlnAsnIleIleLeuAspSerTyrMetGlnHisThrHis                              108510901095                                                                  TGCAGTCTTTATCCTAATCCAAGTAAGAATTGCCGCCCAACACGTGAT3534                          CysSerLeuTyrProAsnProSerLysAsnCysArgProThrArgAsp                              1100110511101115                                                              AAACCTTATTCATACTATCATTCTGATAGAAATGTTTATAAAGAAAAA3582                          LysProTyrSerTyrTyrHisSerAspArgAsnValTyrLysGluLys                              112011251130                                                                  CATAATATGTTGCAATTGAATTTAGAGAAAAAAATTCAACAAAATTGG3630                          HisAsnMetLeuGlnLeuAsnLeuGluLysLysIleGlnGlnAsnTrp                              113511401145                                                                  CTTACTCATCAAATTGTCTTCAATCTTGGTTTTGATGACTTTACTTCA3678                          LeuThrHisGlnIleValPheAsnLeuGlyPheAspAspPheThrSer                              115011551160                                                                  GCGCTTCAGCATAAAGATTATTTAACTCGACGTGTTACCGCTACGGCA3726                          AlaLeuGlnHisLysAspTyrLeuThrArgArgValThrAlaThrAla                              116511701175                                                                  AAGAGTATTTCAGAGAAAGCTAATGAAACAAGAAGAAATGGTTACAAA3774                          LysSerIleSerGluLysAlaAsnGluThrArgArgAsnGlyTyrLys                              1180118511901195                                                              AAACAACCTTACTTATACCCAAAACCAACAGTAGGTTTTGTAGTACAA3822                          LysGlnProTyrLeuTyrProLysProThrValGlyPheValValGln                              120012051210                                                                  GATCATTGTGATTATAAAGGTAACTCCTCTAATTACAGAGACTGTAAA3870                          AspHisCysAspTyrLysGlyAsnSerSerAsnTyrArgAspCysLys                              121512201225                                                                  GTGCGGTTAATTAAAGGGAAAAATTATTATTTCGCAGCACGCAATAAT3918                          ValArgLeuIleLysGlyLysAsnTyrTyrPheAlaAlaArgAsnAsn                              123012351240                                                                  ATGGCATTAGGGAAATACGTTGATTTAGGTTTAGGTATTCGGTATGAC3966                          MetAlaLeuGlyLysTyrValAspLeuGlyLeuGlyIleArgTyrAsp                              124512501255                                                                  GTATCTCGCACAAAAGCTAATGAATCAACTATTAGTGTTGGTAAATTT4014                          ValSerArgThrLysAlaAsnGluSerThrIleSerValGlyLysPhe                              1260126512701275                                                              AAAAATTTCTCTTGGAATACTGGTATTGTCATAAAACCAACGGAATGG4062                          LysAsnPheSerTrpAsnThrGlyIleValIleLysProThrGluTrp                              128012851290                                                                  CTTGATCTTTCTTATCGCCTTTCTACTGGATTTAGAAATCCTAGTTTT4110                          LeuAspLeuSerTyrArgLeuSerThrGlyPheArgAsnProSerPhe                              129513001305                                                                  GCTGAAATGTATGGTTGGCGGTATGGTGGCAATAATAGCGAGGTTTAT4158                          AlaGluMetTyrGlyTrpArgTyrGlyGlyAsnAsnSerGluValTyr                              131013151320                                                                  GTAGGTAAATTTAAGCCTGAAACATCTCGTAACCAAGAGTTTGGTCTC4206                          ValGlyLysPheLysProGluThrSerArgAsnGlnGluPheGlyLeu                              132513301335                                                                  GCTCTAAAAGGGGATTTTGGTAATATTGAGATCAGTCATTTTAGTAAT4254                          AlaLeuLysGlyAspPheGlyAsnIleGluIleSerHisPheSerAsn                              1340134513501355                                                              GCTTATCGAAATCTTATCGCCTTTGCTGAAGAACTTAATAAAAATGGA4302                          AlaTyrArgAsnLeuIleAlaPheAlaGluGluLeuAsnLysAsnGly                              136013651370                                                                  ACTGGAAAGGCCAATTATGGATATCATAATGCACAAAATGCAAAATTA4350                          ThrGlyLysAlaAsnTyrGlyTyrHisAsnAlaGlnAsnAlaLysLeu                              137513801385                                                                  GTTGGCGTAAATATAACTGCGCAATTAGATTTTAATGGTTTATGGAAA4398                          ValGlyValAsnIleThrAlaGlnLeuAspPheAsnGlyLeuTrpLys                              139013951400                                                                  CGTATTCCCTACGGTTGGTATGCAACATTTGCTTATAACCGAGTAAAA4446                          ArgIleProTyrGlyTrpTyrAlaThrPheAlaTyrAsnArgValLys                              140514101415                                                                  GTTAAAGATCAAAAAATCAATGCTGGTTTGGCCTCCGTAAGCAGTTAT4494                          ValLysAspGlnLysIleAsnAlaGlyLeuAlaSerValSerSerTyr                              1420142514301435                                                              TTATTTGATGCCATTCAGCCCAGCCGTTATATCATTGGTTTAGGCTAT4542                          LeuPheAspAlaIleGlnProSerArgTyrIleIleGlyLeuGlyTyr                              144014451450                                                                  GATCATCCAAGTAATACTTGGGGAATTAATACAATGTTTACTCAATCA4590                          AspHisProSerAsnThrTrpGlyIleAsnThrMetPheThrGlnSer                              145514601465                                                                  AAAGCAAAATCTCAAAATGAATTGCTAGGAAAACGTGCATTGGGTAAC4638                          LysAlaLysSerGlnAsnGluLeuLeuGlyLysArgAlaLeuGlyAsn                              147014751480                                                                  AATTCAAGGGATGTAAAATCAACAAGAAAACTTACTCGGGCATGGCAT4686                          AsnSerArgAspValLysSerThrArgLysLeuThrArgAlaTrpHis                              148514901495                                                                  ATCTTAGATGTATCGGGTTATTACATGGCGAATAAAAATATTATGCTT4734                          IleLeuAspValSerGlyTyrTyrMetAlaAsnLysAsnIleMetLeu                              1500150515101515                                                              CGATTAGGGATATATAATTTATTCAACTATCGCTATGTTACTTGGGAA4782                          ArgLeuGlyIleTyrAsnLeuPheAsnTyrArgTyrValThrTrpGlu                              152015251530                                                                  GCGGTGCGTCAAACAGCACAAGGTGCGGTCAATCAACATCAAAATGTT4830                          AlaValArgGlnThrAlaGlnGlyAlaValAsnGlnHisGlnAsnVal                              153515401545                                                                  GGTAGCTATACTCGCTACGCAGCATCAGGACGAAACTATACCTTAACA4878                          GlySerTyrThrArgTyrAlaAlaSerGlyArgAsnTyrThrLeuThr                              155015551560                                                                  TTAGAAATGAAATTCTAAATTAAAATGCGCCAGATGGACTAGACATGCTATA4930                      LeuGluMetLys                                                                  1565                                                                          TCTATACCTTACTGGCGCATCTTTTTCTGTTCTATAATCTGGTTAAGTGAAAAACCAAAC4990              TTGGATTTTTTAGAAGATCTTTCCACGCATTTATTGTAAAATCTCCGACAATTTTTACCG5050              CACTTTTCTCTATTACAAAAACAATAAGGATCCTTTTGTGAATCTCTCA5099                         (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 913 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       MetThrLysLysProTyrPheArgLeuSerIleIleSerCysLeuLeu                              151015                                                                        IleSerCysTyrValLysAlaGluThrGlnSerIleLysAspThrLys                              202530                                                                        GluAlaIleSerSerGluValAspThrGlnSerThrGluAspSerGlu                              354045                                                                        LeuGluThrIleSerValThrAlaGluLysValArgAspArgLysAsp                              505560                                                                        AsnGluValThrGlyLeuGlyLysIleIleLysThrSerGluSerIle                              65707580                                                                      SerArgGluGlnValLeuAsnIleArgAspLeuThrArgTyrAspPro                              859095                                                                        GlyIleSerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSer                              100105110                                                                     IleArgGlyMetAspArgAsnArgValAlaLeuLeuValAspGlyLeu                              115120125                                                                     ProGlnThrGlnSerTyrValValGlnSerProLeuValAlaArgSer                              130135140                                                                     GlyTyrSerGlyThrGlyAlaIleAsnGluIleGluTyrGluAsnVal                              145150155160                                                                  LysAlaValGluIleSerLysGlyGlySerSerSerGluTyrGlyAsn                              165170175                                                                     GlyAlaLeuAlaGlySerValThrPheGlnSerLysSerAlaAlaAsp                              180185190                                                                     IleLeuGluGlyAspLysSerTrpGlyIleGlnThrLysAsnAlaTyr                              195200205                                                                     SerSerLysAsnLysGlyPheThrHisSerLeuAlaValAlaGlyLys                              210215220                                                                     GlnGlyGlyPheGluGlyValAlaIleTyrThrHisArgAsnSerIle                              225230235240                                                                  GluThrGlnValHisLysAspAlaLeuLysGlyValGlnSerTyrAsp                              245250255                                                                     ArgPheIleAlaThrThrGluAspGlnSerAlaTyrPheValMetGln                              260265270                                                                     AspGluCysLeuAspGlyTyrAspLysCysLysThrSerProLysArg                              275280285                                                                     ProAlaThrLeuSerThrGlnArgGluThrValSerValSerAspTyr                              290295300                                                                     ThrGlyAlaAsnArgIleLysProAsnProMetLysTyrGluSerGln                              305310315320                                                                  SerTrpPheLeuArgGlyGlyTyrHisPheSerGluGlnHisTyrIle                              325330335                                                                     GlyGlyIlePheGluPheThrGlnGlnLysPheAspIleArgAspMet                              340345350                                                                     ThrPheProAlaTyrLeuArgProThrGluAspLysAspLeuGlnSer                              355360365                                                                     ArgProPheTyrProLysGlnAspTyrGlyAlaTyrGlnHisIleGly                              370375380                                                                     AspGlyArgGlyValLysTyrAlaSerGlyLeuTyrPheAspGluHis                              385390395400                                                                  HisArgLysGlnArgValGlyIleGluTyrIleTyrGluAsnLysAsn                              405410415                                                                     LysAlaGlyIleIleAspLysAlaValLeuSerAlaAsnGlnGlnAsn                              420425430                                                                     IleIleLeuAspSerTyrMetArgHisThrHisCysSerLeuTyrPro                              435440445                                                                     AsnProSerLysAsnCysArgProThrLeuAspLysProTyrSerTyr                              450455460                                                                     TyrHisSerAspArgAsnValTyrLysGluLysHisAsnMetLeuGln                              465470475480                                                                  LeuAsnLeuGluLysLysIleGlnGlnAsnTrpLeuThrHisGlnIle                              485490495                                                                     AlaPheAsnLeuGlyPheAspAspPheThrSerAlaLeuGlnHisLys                              500505510                                                                     AspTyrLeuThrArgArgValIleAlaThrAlaSerSerIleSerGlu                              515520525                                                                     LysArgGlyGluAlaArgArgAsnGlyLeuGlnSerSerProTyrLeu                              530535540                                                                     TyrProThrProLysAlaGluLeuValGlyGlyAspLeuCysAsnTyr                              545550555560                                                                  GlnGlyLysSerSerAsnTyrSerAspCysLysValArgLeuIleLys                              565570575                                                                     GlyLysAsnTyrTyrPheAlaAlaArgAsnAsnMetAlaLeuGlyLys                              580585590                                                                     TyrValAspLeuGlyLeuGlyMetArgTyrAspValSerArgThrLys                              595600605                                                                     AlaAsnGluSerThrIleSerValGlyLysPheLysAsnPheSerTrp                              610615620                                                                     AsnThrGlyIleValIleLysProThrGluTrpLeuAspLeuSerTyr                              625630635640                                                                  ArgLeuSerThrGlyPheArgAsnProSerPheAlaGluMetTyrGly                              645650655                                                                     TrpArgTyrGlyGlyLysAspThrAspValTyrIleGlyLysPheLys                              660665670                                                                     ProGluThrSerArgAsnGlnGluPheGlyLeuAlaLeuLysGlyAsp                              675680685                                                                     PheGlyAsnIleGluIleSerHisPheSerAsnAlaTyrArgAsnLeu                              690695700                                                                     IleAlaPheAlaGluGluLeuSerLysAsnGlyThrThrGlyLysGly                              705710715720                                                                  AsnTyrGlyTyrHisAsnAlaGlnAsnAlaLysLeuValGlyValAsn                              725730735                                                                     IleThrAlaGlnLeuAspPheAsnGlyLeuTrpLysArgIleProTyr                              740745750                                                                     GlyTrpTyrAlaThrPheAlaTyrAsnArgValLysValLysAspGln                              755760765                                                                     LysIleAsnAlaGlyLeuAlaSerValSerSerTyrLeuPheAspAla                              770775780                                                                     IleGlnProSerArgTyrIleIleGlyLeuGlyTyrAspHisProSer                              785790795800                                                                  AsnThrTrpGlyIleLysThrMetPheThrGlnSerLysAlaLysSer                              805810815                                                                     GlnAsnGluLeuLeuGlyLysArgAlaLeuGlyAsnAsnSerArgAsn                              820825830                                                                     ValLysSerThrArgLysLeuThrArgAlaTrpHisIleLeuAspVal                              835840845                                                                     SerGlyTyrTyrMetValAsnArgSerIleLeuPheArgLeuGlyVal                              850855860                                                                     TyrAsnLeuLeuAsnTyrArgTyrValThrTrpGluAlaValArgGln                              865870875880                                                                  ThrAlaGlnGlyAlaValAsnGlnHisGlnAsnValGlyAsnTyrThr                              885890895                                                                     ArgTyrAlaAlaSerGlyArgAsnTyrThrLeuThrLeuGluMetLys                              900905910                                                                     Phe                                                                           (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 644 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnThr                              202530                                                                        ProSerSerLysProArgTyrGlnAspAspThrSerSerSerArgThr                              354045                                                                        LysSerLysLeuGluLysLeuSerIleProSerLeuGlyGlyGlyMet                              505560                                                                        LysLeuAlaAlaLeuAsnLeuPheAspArgAsnLysProSerLeuLeu                              65707580                                                                      AsnGluAspSerTyrMetIlePheSerSerArgSerThrIleGluGlu                              859095                                                                        AspValLysAsnAspAsnGlnAsnGlyGluHisProIleAspSerIle                              100105110                                                                     ValAspProArgAlaProAsnSerAsnGluAsnArgHisGlyGlnLys                              115120125                                                                     TyrValTyrSerGlyLeuTyrTyrIleGlnSerTrpSerLeuArgAsp                              130135140                                                                     LeuProAsnLysLysPheTyrSerGlyTyrTyrGlyTyrAlaTyrTyr                              145150155160                                                                  PheGlyAsnThrThrAlaSerAlaLeuProValGlyGlyValAlaThr                              165170175                                                                     TyrLysGlyThrTrpSerPheIleThrAlaAlaGluAsnGlyLysAsn                              180185190                                                                     TyrGluLeuLeuArgAsnSerGlyGlyGlyGlnAlaTyrSerArgArg                              195200205                                                                     SerAlaThrProGluAspIleAspLeuAspArgLysThrGlyLeuThr                              210215220                                                                     SerGluPheThrValAsnPheGlyThrLysLysLeuThrGlyGlyLeu                              225230235240                                                                  TyrTyrAsnLeuArgGluThrAspAlaAsnLysSerGlnAsnArgThr                              245250255                                                                     HisLysLeuTyrAspLeuGluAlaAspValHisSerAsnArgPheArg                              260265270                                                                     GlyLysValLysProThrLysLysGluSerSerGluGluHisProPhe                              275280285                                                                     ThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProGluGlyGln                              290295300                                                                     GluLeuGlyGlyLysPheLeuAlaHisAspLysLysValLeuGlyVal                              305310315320                                                                  PheSerAlaLysGluGlnGlnGluThrSerGluAsnLysLysLeuPro                              325330335                                                                     LysGluThrLeuIleAspGlyLysLeuThrThrPheLysThrThrAsn                              340345350                                                                     AlaThrAlaAsnAlaThrThrAspAlaThrThrSerThrThrAlaSer                              355360365                                                                     ThrLysThrAspThrThrThrAsnAlaThrAlaAsnThrGluAsnPhe                              370375380                                                                     ThrThrLysAspIleProSerLeuGlyGluAlaAspTyrLeuLeuIle                              385390395400                                                                  AspAsnTyrProValProLeuPheProGluSerGlyAspPheIleSer                              405410415                                                                     SerLysHisHisThrValGlyLysLysThrTyrGlnValGluAlaCys                              420425430                                                                     CysSerAsnLeuSerTyrValLysPheGlyMetTyrTyrGluAlaPro                              435440445                                                                     ProLysGluGluGluLysGluLysGluLysAspLysAspLysGluLys                              450455460                                                                     GluLysGlnAlaThrThrSerIleLysThrTyrTyrGlnPheLeuLeu                              465470475480                                                                  GlyLeuArgThrProSerSerGluIleProLysGluGlySerAlaLys                              485490495                                                                     TyrHisGlyAsnTrpPheGlyTyrIleSerAspGlyGluThrSerTyr                              500505510                                                                     SerAlaSerGlyAspLysGluArgSerLysAsnAlaValAlaGluPhe                              515520525                                                                     AsnValAsnPheAlaGluLysThrLeuThrGlyGluLeuLysArgHis                              530535540                                                                     AspThrGlnAsnProValPheLysIleAsnAlaThrPheGlnSerGly                              545550555560                                                                  LysAsnAspPheThrGlyThrAlaThrAlaLysAspLeuAlaIleAsp                              565570575                                                                     GlyLysAsnThrGlnGlyThrSerLysValAsnPheThrAlaThrVal                              580585590                                                                     AsnGlyAlaPheTyrGlyProHisAlaThrGluLeuGlyGlyTyrPhe                              595600605                                                                     ThrTyrAsnGlyAsnAsnProThrAspLysAsnSerSerSerAsnSer                              610615620                                                                     GluLysAlaArgAlaAlaValValPheGlyAlaLysLysGlnGlnVal                              625630635640                                                                  GluThrThrLys                                                                  (2) INFORMATION FOR SEQ ID NO:7:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 912 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                       MetThrLysLysProTyrPheArgLeuSerIleIleSerCysLeuLeu                              151015                                                                        IleSerCysTyrValLysAlaGluThrGlnSerIleLysAspThrLys                              202530                                                                        GluAlaIleSerSerGluValAspThrGlnSerThrGluAspSerGlu                              354045                                                                        LeuGluThrIleSerValThrAlaGluLysIleArgAspArgLysAsp                              505560                                                                        AsnGluValThrGlyLeuGlyLysIleIleLysThrSerGluSerIle                              65707580                                                                      SerArgGluGlnValLeuAsnIleArgAspLeuThrArgTyrAspPro                              859095                                                                        GlyIleSerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSer                              100105110                                                                     IleArgGlyMetAspArgAsnArgValAlaLeuLeuValAspGlyLeu                              115120125                                                                     ProGlnThrGlnSerTyrValValGlnSerProLeuValAlaArgSer                              130135140                                                                     GlyTyrSerGlyThrGlyAlaIleAsnGluIleGluTyrGluAsnVal                              145150155160                                                                  LysAlaValGluIleSerLysGlyGlySerSerSerGluTyrGlyAsn                              165170175                                                                     GlyAlaLeuAlaGlySerValThrPheGlnSerLysSerAlaAlaAsp                              180185190                                                                     IleLeuGluGlyAspLysSerTrpGlyIleGlnThrLysAsnAlaTyr                              195200205                                                                     SerSerLysAsnLysGlyPheThrHisSerLeuAlaValAlaGlyLys                              210215220                                                                     GlnGlyGlyPheGluGlyLeuAlaIleTyrThrGlnArgAsnSerIle                              225230235240                                                                  GluThrGlnValHisLysAspAlaLeuLysGlyValGlnSerTyrAsp                              245250255                                                                     ArgLeuIleAlaThrThrAspLysSerSerGlyTyrPheValIleGln                              260265270                                                                     GlyGluCysProAsnGlyAspAspLysCysAlaAlaLysProProAla                              275280285                                                                     ThrLeuSerThrGlnSerGluThrValSerValSerAspTyrThrGly                              290295300                                                                     AlaAsnArgIleLysProAsnProMetLysTyrGluSerGlnSerTrp                              305310315320                                                                  PheLeuArgGlyGlyTyrHisPheSerGluGlnHisTyrIleGlyGly                              325330335                                                                     IlePheGluPheThrGlnGlnLysPheAspIleArgAspMetThrPhe                              340345350                                                                     ProAlaTyrLeuSerProThrGluArgArgAspAspSerSerArgSer                              355360365                                                                     PheTyrProMetGlnAspHisGlyAlaTyrGlnHisIleGluAspGly                              370375380                                                                     ArgGlyValLysTyrAlaSerGlyLeuTyrPheAspGluHisHisArg                              385390395400                                                                  LysGlnArgValGlyIleGluTyrIleTyrGluAsnLysAsnLysAla                              405410415                                                                     GlyIleIleAspLysAlaValLeuSerAlaAsnGlnGlnAsnIleIle                              420425430                                                                     LeuAspSerTyrMetArgHisThrHisCysSerLeuTyrProAsnPro                              435440445                                                                     SerLysAsnCysArgProThrLeuAspLysProTyrSerTyrTyrArg                              450455460                                                                     SerAspArgAsnValTyrLysGluLysHisAsnMetLeuGlnLeuAsn                              465470475480                                                                  LeuGluLysLysIleGlnGlnAsnTrpLeuThrHisGlnIleValPhe                              485490495                                                                     AsnLeuGlyPheAspAspPheThrSerAlaLeuGlnHisLysAspTyr                              500505510                                                                     LeuThrArgArgValIleAlaThrAlaAspSerIleProArgLysPro                              515520525                                                                     GlyGluThrGlyLysProArgAsnGlyLeuGlnSerGlnProTyrLeu                              530535540                                                                     TyrProLysProGluProTyrPheAlaGlyGlnAspHisCysAsnTyr                              545550555560                                                                  GlnGlySerSerSerAsnTyrArgAspCysLysValArgLeuIleLys                              565570575                                                                     GlyLysAsnTyrTyrPheAlaAlaArgAsnAsnMetAlaLeuGlyLys                              580585590                                                                     TyrValAspLeuGlyLeuGlyIleArgTyrAspValSerArgThrLys                              595600605                                                                     AlaAsnGluSerThrIleSerValGlyLysPheLysAsnPheSerTrp                              610615620                                                                     AsnThrGlyIleValIleLysProThrGluTrpLeuAspLeuSerTyr                              625630635640                                                                  ArgLeuSerThrGlyPheArgAsnProSerPheSerGluMetTyrGly                              645650655                                                                     TrpArgTyrGlyGlyLysAsnAspGluValTyrValGlyLysPheLys                              660665670                                                                     ProGluThrSerArgAsnGlnGluPheGlyLeuAlaLeuLysGlyAsp                              675680685                                                                     PheGlyAsnIleGluIleSerHisPheSerAsnAlaTyrArgAsnLeu                              690695700                                                                     IleAlaPheAlaGluGluLeuSerLysAsnGlyThrGlyLysGlyAsn                              705710715720                                                                  TyrGlyTyrHisAsnAlaGlnAsnAlaLysLeuValGlyValAsnIle                              725730735                                                                     ThrAlaGlnLeuAspPheAsnGlyLeuTrpLysArgIleProTyrGly                              740745750                                                                     TrpTyrAlaThrPheAlaTyrAsnGlnValLysValLysAspGlnLys                              755760765                                                                     IleAsnAlaGlyLeuAlaSerValSerSerTyrLeuPheAspAlaIle                              770775780                                                                     GlnProSerArgTyrIleIleGlyLeuGlyTyrAspHisProSerAsn                              785790795800                                                                  ThrTrpGlyIleAsnThrMetPheThrGlnSerLysAlaLysSerGln                              805810815                                                                     AsnGluLeuLeuGlyLysArgAlaLeuGlyAsnAsnSerArgAspVal                              820825830                                                                     LysSerThrArgLysLeuThrArgAlaTrpHisIleLeuAspValSer                              835840845                                                                     GlyTyrTyrMetAlaAsnLysAsnIleMetLeuArgLeuGlyIleTyr                              850855860                                                                     AsnLeuPheAsnTyrArgTyrValThrTrpGluAlaValArgGlnThr                              865870875880                                                                  AlaGlnGlyAlaValAsnGlnHisGlnAsnValGlySerTyrThrArg                              885890895                                                                     TyrAlaAlaSerGlyArgAsnTyrThrLeuThrLeuGluMetLysPhe                              900905910                                                                     (2) INFORMATION FOR SEQ ID NO:8:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 660 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                       MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnThr                              202530                                                                        ProSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArgLys                              354045                                                                        LysSerAsnLeuLysLysLeuPheIleProSerLeuGlyGlyGlyMet                              505560                                                                        LysLeuValAlaGlnAsnLeuArgGlyAsnLysGluProSerPheLeu                              65707580                                                                      AsnGluAspAspTyrIleSerTyrPheSerSerLeuSerThrIleGlu                              859095                                                                        LysAspValLysAspAsnAsnLysAsnGlyAlaAspLeuIleGlySer                              100105110                                                                     IleAspGluProSerThrThrAsnProProGluLysHisHisGlyGln                              115120125                                                                     LysTyrValTyrSerGlyLeuTyrTyrThrProSerTrpSerLeuAsn                              130135140                                                                     AspSerLysAsnLysPheTyrLeuGlyTyrTyrGlyTyrAlaPheTyr                              145150155160                                                                  TyrGlyAsnLysThrAlaThrAsnLeuProValAsnGlyValAlaLys                              165170175                                                                     TyrLysGlyThrTrpAspPheIleThrAlaThrLysAsnGlyLysArg                              180185190                                                                     TyrProLeuLeuSerAsnGlySerHisAlaTyrTyrArgArgSerAla                              195200205                                                                     IleProGluAspIleAspLeuGluAsnAspSerLysAsnGlyAspIle                              210215220                                                                     GlyLeuIleSerGluPheSerAlaAspPheGlyThrLysLysLeuThr                              225230235240                                                                  GlyGlnLeuSerTyrThrLysArgLysThrAsnAsnGlnProTyrGlu                              245250255                                                                     LysLysLysLeuTyrAspIleAspAlaAspIleTyrSerAsnArgPhe                              260265270                                                                     ArgGlyThrValLysProThrGluLysAspSerGluGluHisProPhe                              275280285                                                                     ThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsnAlaGlu                              290295300                                                                     GluLeuGlyGlyLysPheLeuAlaThrAspAsnArgValPheGlyVal                              305310315320                                                                  PheSerAlaLysGluThrGluGluThrLysLysGluAlaLeuSerLys                              325330335                                                                     GluThrLeuIleAspGlyLysLeuIleThrPheSerThrLysLysThr                              340345350                                                                     AspAlaLysThrAsnAlaThrThrSerThrAlaAlaAsnThrThrThr                              355360365                                                                     AspThrThrAlaAsnThrIleThrAspGluLysAsnPheLysThrGlu                              370375380                                                                     AspIleSerSerPheGlyGluAlaAspTyrLeuLeuIleAspLysTyr                              385390395400                                                                  ProIleProLeuLeuProAspLysAsnThrAsnAspPheIleSerSer                              405410415                                                                     LysHisHisThrValGlyAsnLysArgTyrLysValGluAlaCysCys                              420425430                                                                     SerAsnLeuSerTyrValLysPheGlyMetTyrTyrGluAspProLeu                              435440445                                                                     LysGluLysGluThrGluThrGluThrGluThrGluLysAspLysGlu                              450455460                                                                     LysGluLysGluLysAspLysAspLysGluLysGlnThrAlaAlaThr                              465470475480                                                                  ThrAsnThrTyrTyrGlnPheLeuLeuGlyHisArgThrProLysAsp                              485490495                                                                     AspIleProLysThrGlySerAlaLysTyrHisGlySerTrpPheGly                              500505510                                                                     TyrIleThrAspGlyLysThrSerTyrSerProSerGlyAspLysLys                              515520525                                                                     ArgAspLysAsnAlaValAlaGluPheAsnValAspPheAlaGluLys                              530535540                                                                     LysLeuThrGlyGluLeuLysArgHisAspThrGlyAsnProValPhe                              545550555560                                                                  SerIleGluAlaAsnPheAsnAsnSerSerAsnAlaPheThrGlyThr                              565570575                                                                     AlaThrAlaThrAsnPheValIleAspGlyLysAsnSerGlnAsnLys                              580585590                                                                     AsnThrProIleAsnIleThrThrLysValAsnGlyAlaPheTyrGly                              595600605                                                                     ProLysAlaSerGluLeuGlyGlyTyrPheThrTyrAsnGlyAsnSer                              610615620                                                                     ThrAlaThrAsnSerGluSerSerSerThrValSerSerSerSerAsn                              625630635640                                                                  SerLysAsnAlaArgAlaAlaValValPheGlyAlaArgGlnGlnVal                              645650655                                                                     GluThrThrLys                                                                  660                                                                           (2) INFORMATION FOR SEQ ID NO:9:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 912 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                       MetThrLysLysProTyrPheArgLeuSerIleIleSerCysLeuLeu                              151015                                                                        IleSerCysTyrValLysAlaGluThrGlnSerIleLysAspThrLys                              202530                                                                        GluAlaIleSerSerGluValAspThrGlnSerThrGluAspSerGlu                              354045                                                                        LeuGluThrIleSerValThrAlaGluLysIleArgAspArgLysAsp                              505560                                                                        AsnGluValThrGlyLeuGlyLysIleIleLysThrSerGluSerIle                              65707580                                                                      SerArgGluGlnValLeuAsnIleArgAspLeuThrArgTyrAspPro                              859095                                                                        GlyIleSerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSer                              100105110                                                                     IleArgGlyMetAspArgAsnArgValAlaLeuLeuValAspGlyLeu                              115120125                                                                     ProGlnThrGlnSerTyrValValGlnSerProLeuValAlaArgSer                              130135140                                                                     GlyTyrSerGlyThrGlyAlaIleAsnGluIleGluTyrGluAsnVal                              145150155160                                                                  LysAlaValGluIleSerLysGlyGlySerSerSerGluTyrGlyAsn                              165170175                                                                     GlyAlaLeuAlaGlySerValThrPheGlnSerLysSerAlaAlaAsp                              180185190                                                                     IleLeuGluGlyAspLysSerTrpGlyIleGlnThrLysAsnAlaTyr                              195200205                                                                     SerSerLysAsnLysGlyPheThrHisSerLeuAlaValAlaGlyLys                              210215220                                                                     GlnGlyGlyPheGluGlyLeuAlaIleTyrThrGlnArgAsnSerIle                              225230235240                                                                  GluThrGlnValHisLysAspAlaLeuLysGlyValGlnSerTyrAsp                              245250255                                                                     ArgLeuIleAlaThrThrAspLysSerSerGlyTyrPheValIleGln                              260265270                                                                     GlyGluCysProAsnGlyAspAspLysCysAlaAlaLysProProAla                              275280285                                                                     ThrLeuSerThrGlnSerGluThrValSerValSerAspTyrThrGly                              290295300                                                                     AlaAsnArgIleLysProAsnProMetLysTyrGluSerGlnSerTrp                              305310315320                                                                  PheLeuArgGlyGlyTyrHisPheSerGluGlnHisTyrIleGlyGly                              325330335                                                                     IlePheGluPheThrGlnGlnLysPheAspIleArgAspMetThrPhe                              340345350                                                                     ProAlaTyrLeuSerProThrGluArgArgAspAspSerSerArgSer                              355360365                                                                     PheTyrProMetGlnAspHisGlyAlaTyrGlnHisIleGluAspGly                              370375380                                                                     ArgGlyValLysTyrAlaSerGlyLeuTyrPheAspGluHisHisArg                              385390395400                                                                  LysGlnArgValGlyIleGluTyrIleTyrGluAsnLysAsnLysAla                              405410415                                                                     GlyIleIleAspLysAlaValLeuSerAlaAsnGlnGlnAsnIleIle                              420425430                                                                     LeuAspSerTyrMetArgHisThrHisCysSerLeuTyrProAsnPro                              435440445                                                                     SerLysAsnCysArgProThrLeuAspLysProTyrSerTyrTyrArg                              450455460                                                                     SerAspArgAsnValTyrLysGluLysHisAsnMetLeuGlnLeuAsn                              465470475480                                                                  LeuGluLysLysIleGlnGlnAsnTrpLeuThrHisGlnIleValPhe                              485490495                                                                     AsnLeuGlyPheAspAspPheThrSerAlaLeuGlnHisLysAspTyr                              500505510                                                                     LeuThrArgArgValIleAlaThrAlaAspSerIleProArgLysPro                              515520525                                                                     GlyGluThrGlyLysProArgAsnGlyLeuGlnSerGlnProTyrLeu                              530535540                                                                     TyrProLysProGluProTyrPheAlaGlyGlnAspHisCysAsnTyr                              545550555560                                                                  GlnGlySerSerSerAsnTyrArgAspCysLysValArgLeuIleLys                              565570575                                                                     GlyLysAsnTyrTyrPheAlaAlaArgAsnAsnMetAlaLeuGlyLys                              580585590                                                                     TyrValAspLeuGlyLeuGlyIleArgTyrAspValSerArgThrLys                              595600605                                                                     AlaAsnGluSerThrIleSerValGlyLysPheLysAsnPheSerTrp                              610615620                                                                     AsnThrGlyIleValIleLysProThrGluTrpLeuAspLeuSerTyr                              625630635640                                                                  ArgLeuSerThrGlyPheArgAsnProSerPheSerGluMetTyrGly                              645650655                                                                     TrpArgTyrGlyGlyLysAsnAspGluValTyrValGlyLysPheLys                              660665670                                                                     ProGluThrSerArgAsnGlnGluPheGlyLeuAlaLeuLysGlyAsp                              675680685                                                                     PheGlyAsnIleGluIleSerHisPheSerAsnAlaTyrArgAsnLeu                              690695700                                                                     IleAlaPheAlaGluGluLeuSerLysAsnGlyThrGlyLysGlyAsn                              705710715720                                                                  TyrGlyTyrHisAsnAlaGlnAsnAlaLysLeuValGlyValAsnIle                              725730735                                                                     ThrAlaGlnLeuAspPheAsnGlyLeuTrpLysArgIleProTyrGly                              740745750                                                                     TrpTyrAlaThrPheAlaTyrAsnGlnValLysValLysAspGlnLys                              755760765                                                                     IleAsnAlaGlyLeuAlaSerValSerSerTyrLeuPheAspAlaIle                              770775780                                                                     GlnProSerArgTyrIleIleGlyLeuGlyTyrAspHisProSerAsn                              785790795800                                                                  ThrTrpGlyIleAsnThrMetPheThrGlnSerLysAlaLysSerGln                              805810815                                                                     AsnGluLeuLeuGlyLysArgAlaLeuGlyAsnAsnSerArgAspVal                              820825830                                                                     LysSerThrArgLysLeuThrArgAlaTrpHisIleLeuAspValSer                              835840845                                                                     GlyTyrTyrMetAlaAsnLysAsnIleMetLeuArgLeuGlyIleTyr                              850855860                                                                     AsnLeuPheAsnTyrArgTyrValThrTrpGluAlaValArgGlnThr                              865870875880                                                                  AlaGlnGlyAlaValAsnGlnHisGlnAsnValGlySerTyrThrArg                              885890895                                                                     TyrAlaAlaSerGlyArgAsnTyrThrLeuThrLeuGluMetLysPhe                              900905910                                                                     (2) INFORMATION FOR SEQ ID NO:10:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 660 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                      MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnThr                              202530                                                                        ProSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArgLys                              354045                                                                        LysSerAsnLeuLysLysLeuPheIleProSerLeuGlyGlyGlyMet                              505560                                                                        LysLeuValAlaGlnAsnLeuArgGlyAsnLysGluProSerPheLeu                              65707580                                                                      AsnGluAspAspTyrIleSerTyrPheSerSerLeuSerThrIleGlu                              859095                                                                        LysAspValLysAspAsnAsnLysAsnGlyAlaAspLeuIleGlySer                              100105110                                                                     IleAspGluProSerThrThrAsnProProGluLysHisHisGlyGln                              115120125                                                                     LysTyrValTyrSerGlyLeuTyrTyrThrProSerTrpSerLeuAsn                              130135140                                                                     AspSerLysAsnLysPheTyrLeuGlyTyrTyrGlyTyrAlaPheTyr                              145150155160                                                                  TyrGlyAsnLysThrAlaThrAsnLeuProValAsnGlyValAlaLys                              165170175                                                                     TyrLysGlyThrTrpAspPheIleThrAlaThrLysAsnGlyLysArg                              180185190                                                                     TyrProLeuLeuSerAsnGlySerHisAlaTyrTyrArgArgSerAla                              195200205                                                                     IleProGluAspIleAspLeuGluAsnAspSerLysAsnGlyAspIle                              210215220                                                                     GlyLeuIleSerGluPheSerAlaAspPheGlyThrLysLysLeuThr                              225230235240                                                                  GlyGlnLeuSerTyrThrLysArgLysThrAsnAsnGlnProTyrGlu                              245250255                                                                     LysLysLysLeuTyrAspIleAspAlaAspIleTyrSerAsnArgPhe                              260265270                                                                     ArgGlyThrValLysProThrGluLysAspSerGluGluHisProPhe                              275280285                                                                     ThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsnAlaGlu                              290295300                                                                     GluLeuGlyGlyLysPheLeuAlaThrAspAsnArgValPheGlyVal                              305310315320                                                                  PheSerAlaLysGluThrGluGluThrLysLysGluAlaLeuSerLys                              325330335                                                                     GluThrLeuIleAspGlyLysLeuIleThrPheSerThrLysLysThr                              340345350                                                                     AspAlaLysThrAsnAlaThrThrSerThrAlaAlaAsnThrThrThr                              355360365                                                                     AspThrThrAlaAsnThrIleThrAspGluLysAsnPheLysThrGlu                              370375380                                                                     AspIleSerSerPheGlyGluAlaAspTyrLeuLeuIleAspLysTyr                              385390395400                                                                  ProIleProLeuLeuProAspLysAsnThrAsnAspPheIleSerSer                              405410415                                                                     LysHisHisThrValGlyAsnLysArgTyrLysValGluAlaCysCys                              420425430                                                                     SerAsnLeuSerTyrValLysPheGlyMetTyrTyrGluAspProLeu                              435440445                                                                     LysGluLysGluThrGluThrGluThrGluThrGluLysAspLysGlu                              450455460                                                                     LysGluLysGluLysAspLysAspLysGluLysGlnThrAlaAlaThr                              465470475480                                                                  ThrAsnThrTyrTyrGlnPheLeuLeuGlyHisArgThrProLysAsp                              485490495                                                                     AspIleProLysThrGlySerAlaLysTyrHisGlySerTrpPheGly                              500505510                                                                     TyrIleThrAspGlyLysThrSerTyrSerProSerGlyAspLysLys                              515520525                                                                     ArgAspLysAsnAlaValAlaGluPheAsnValAspPheAlaGluLys                              530535540                                                                     LysLeuThrGlyGluLeuLysArgHisAspThrGlyAsnProValPhe                              545550555560                                                                  SerIleGluAlaAsnPheAsnAsnSerSerAsnAlaPheThrGlyThr                              565570575                                                                     AlaThrAlaThrAsnPheValIleAspGlyLysAsnSerGlnAsnLys                              580585590                                                                     AsnThrProIleAsnIleThrThrLysValAsnGlyAlaPheTyrGly                              595600605                                                                     ProLysAlaSerGluLeuGlyGlyTyrPheThrTyrAsnGlyAsnSer                              610615620                                                                     ThrAlaThrAsnSerGluSerSerSerThrValSerSerSerSerAsn                              625630635640                                                                  SerLysAsnAlaArgAlaAlaValValPheGlyAlaArgGlnGlnVal                              645650655                                                                     GluThrThrLys                                                                  660                                                                           (2) INFORMATION FOR SEQ ID NO:11:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 914 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                      MetThrLysLysProTyrPheArgLeuSerIleIleSerCysLeuLeu                              151015                                                                        IleSerCysTyrValLysAlaGluThrGlnSerIleLysAspThrLys                              202530                                                                        GluAlaIleSerSerGluValAspThrGlnSerThrGluAspSerGlu                              354045                                                                        LeuGluThrIleSerValThrAlaGluLysIleArgAspArgLysAsp                              505560                                                                        AsnGluValThrGlyLeuGlyLysIleIleLysThrSerGluSerIle                              65707580                                                                      SerArgGluGlnValLeuAsnIleArgAspLeuThrArgTyrAspPro                              859095                                                                        GlyIleSerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSer                              100105110                                                                     IleArgGlyMetAspArgAsnArgValAlaLeuLeuValAspGlyLeu                              115120125                                                                     ProGlnThrGlnSerTyrValValGlnSerProLeuValAlaArgSer                              130135140                                                                     GlyTyrSerGlyThrGlyAlaIleAsnGluIleGluTyrGluAsnVal                              145150155160                                                                  LysAlaValGluIleSerLysGlyGlySerSerSerGluTyrGlyAsn                              165170175                                                                     GlyAlaLeuAlaGlySerValThrPheGlnSerLysSerAlaAlaAsp                              180185190                                                                     IleLeuGluGlyAspLysSerTrpGlyIleGlnThrLysAsnAlaTyr                              195200205                                                                     SerSerLysAsnLysGlyPheThrHisSerLeuAlaValAlaGlyLys                              210215220                                                                     GlnGlyGlyPheAspGlyValAlaIleTyrThrGlnArgAsnSerIle                              225230235240                                                                  GluThrGlnValHisLysAspAlaLeuLysGlyValGlnSerTyrHis                              245250255                                                                     ArgLeuIleAlaLysProGluAspGlnSerAlaTyrPheValMetGln                              260265270                                                                     AspGluCysProLysProAspAspTyrAsnSerCysLeuProPheAla                              275280285                                                                     LysArgProAlaIleLeuSerSerGlnArgGluThrValSerValSer                              290295300                                                                     AspTyrThrGlyAlaAsnArgIleLysProAsnProMetLysTyrGlu                              305310315320                                                                  SerGlnSerTrpPheLeuArgGlyGlyTyrHisPheSerGluGlnHis                              325330335                                                                     TyrIleGlyGlyIlePheGluPheThrGlnGlnLysPheAspIleArg                              340345350                                                                     AspMetThrPheProAlaTyrLeuArgSerThrGluLysArgAspAsp                              355360365                                                                     SerSerGlySerPheTyrProLysGlnAspTyrGlyAlaTyrGlnArg                              370375380                                                                     IleGluAspGlyArgGlyValAsnTyrAlaSerGlyLeuTyrPheAsp                              385390395400                                                                  GluHisHisArgLysGlnArgValGlyIleGluTyrIleTyrGluAsn                              405410415                                                                     LysAsnLysAlaGlyIleIleAspLysAlaValLeuSerAlaAsnGln                              420425430                                                                     GlnAsnIleIleLeuAspSerTyrMetGlnHisThrHisCysSerLeu                              435440445                                                                     TyrProAsnProSerLysAsnCysArgProThrArgAspLysProTyr                              450455460                                                                     SerTyrTyrHisSerAspArgAsnValTyrLysGluLysHisAsnMet                              465470475480                                                                  LeuGlnLeuAsnLeuGluLysLysIleGlnGlnAsnTrpLeuThrHis                              485490495                                                                     GlnIleValPheAsnLeuGlyPheAspAspPheThrSerAlaLeuGln                              500505510                                                                     HisLysAspTyrLeuThrArgArgValThrAlaThrAlaLysSerIle                              515520525                                                                     SerGluLysAlaAsnGluThrArgArgAsnGlyTyrLysLysGlnPro                              530535540                                                                     TyrLeuTyrProLysProThrValGlyPheValValGlnAspHisCys                              545550555560                                                                  AspTyrLysGlyAsnSerSerAsnTyrArgAspCysLysValArgLeu                              565570575                                                                     IleLysGlyLysAsnTyrTyrPheAlaAlaArgAsnAsnMetAlaLeu                              580585590                                                                     GlyLysTyrValAspLeuGlyLeuGlyIleArgTyrAspValSerArg                              595600605                                                                     ThrLysAlaAsnGluSerThrIleSerValGlyLysPheLysAsnPhe                              610615620                                                                     SerTrpAsnThrGlyIleValIleLysProThrGluTrpLeuAspLeu                              625630635640                                                                  SerTyrArgLeuSerThrGlyPheArgAsnProSerPheAlaGluMet                              645650655                                                                     TyrGlyTrpArgTyrGlyGlyAsnAsnSerGluValTyrValGlyLys                              660665670                                                                     PheLysProGluThrSerArgAsnGlnGluPheGlyLeuAlaLeuLys                              675680685                                                                     GlyAspPheGlyAsnIleGluIleSerHisPheSerAsnAlaTyrArg                              690695700                                                                     AsnLeuIleAlaPheAlaGluGluLeuAsnLysAsnGlyThrGlyLys                              705710715720                                                                  AlaAsnTyrGlyTyrHisAsnAlaGlnAsnAlaLysLeuValGlyVal                              725730735                                                                     AsnIleThrAlaGlnLeuAspPheAsnGlyLeuTrpLysArgIlePro                              740745750                                                                     TyrGlyTrpTyrAlaThrPheAlaTyrAsnArgValLysValLysAsp                              755760765                                                                     GlnLysIleAsnAlaGlyLeuAlaSerValSerSerTyrLeuPheAsp                              770775780                                                                     AlaIleGlnProSerArgTyrIleIleGlyLeuGlyTyrAspHisPro                              785790795800                                                                  SerAsnThrTrpGlyIleAsnThrMetPheThrGlnSerLysAlaLys                              805810815                                                                     SerGlnAsnGluLeuLeuGlyLysArgAlaLeuGlyAsnAsnSerArg                              820825830                                                                     AspValLysSerThrArgLysLeuThrArgAlaTrpHisIleLeuAsp                              835840845                                                                     ValSerGlyTyrTyrMetAlaAsnLysAsnIleMetLeuArgLeuGly                              850855860                                                                     IleTyrAsnLeuPheAsnTyrArgTyrValThrTrpGluAlaValArg                              865870875880                                                                  GlnThrAlaGlnGlyAlaValAsnGlnHisGlnAsnValGlySerTyr                              885890895                                                                     ThrArgTyrAlaAlaSerGlyArgAsnTyrThrLeuThrLeuGluMet                              900905910                                                                     LysPhe                                                                        (2) INFORMATION FOR SEQ ID NO:12:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 654 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                      MetLysSerValProLeuIleThrGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlyGlySerPheAspValAspAspValSerAsn                              202530                                                                        ProSerSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArg                              354045                                                                        ThrLysSerAspLeuGluLysLeuPheIleProSerLeuGlyGlyGly                              505560                                                                        MetLysLeuValAlaGlnAsnPheIleGlyAlaArgGluProSerPhe                              65707580                                                                      LeuAsnGluAspGlyTyrMetIlePheSerSerLeuSerThrIleGlu                              859095                                                                        GluAspValGluLysValLysAsnAsnAsnLysAsnGlyGlyArgLeu                              100105110                                                                     IleGlySerIleGluGluProAsnGlyThrSerGlnAsnSerAsnSer                              115120125                                                                     GlnGluTyrValTyrSerGlyLeuTyrTyrIleAspSerTrpArgAsp                              130135140                                                                     TyrLysLysGluGluGlnLysAlaTyrThrGlyTyrTyrGlyTyrAla                              145150155160                                                                  PheTyrTyrGlyAsnGluThrAlaLysAsnLeuProValLysGlyVal                              165170175                                                                     AlaLysTyrLysGlyThrTrpAsnPheIleThrAlaThrGluAsnGly                              180185190                                                                     LysArgTyrSerLeuPheSerAsnSerIleGlyGlnAlaTyrSerArg                              195200205                                                                     ArgSerAlaIleSerGluAspIleTyrAsnLeuGluAsnGlyAspAla                              210215220                                                                     GlyLeuIleSerGluPheSerValAspPheGlyLysLysGluLeuThr                              225230235240                                                                  GlyGluLeuTyrTyrAsnGluArgLysThrSerValAsnGluSerGln                              245250255                                                                     AsnThrThrHisLysLeuTyrThrLeuGluAlaLysValTyrSerAsn                              260265270                                                                     ArgPheArgGlyLysValLysProThrLysThrLysSerGluAspHis                              275280285                                                                     ProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsn                              290295300                                                                     AlaGluGluLeuGlyGlyLysPheLeuAlaAsnAspGluLysValPhe                              305310315320                                                                  GlyValPheSerAlaLysGluAspProGlnAsnProGluAsnGlnLys                              325330335                                                                     LeuSerThrGluThrLeuIleAspGlyLysLeuIleThrPheLysArg                              340345350                                                                     ThrAspAlaThrThrAsnAlaThrThrAspAlaLysThrSerAlaThr                              355360365                                                                     ThrAspAlaThrSerThrThrAlaAsnLysLysThrAspAlaGluAsn                              370375380                                                                     PheLysThrGluAspIleProSerPheGlyGluAlaAspTyrLeuLeu                              385390395400                                                                  IleGlyAsnGlnProIleProLeuLeuProGluLysAsnThrAspAsp                              405410415                                                                     PheIleSerSerLysHisHisThrValGlyGlyLysThrTyrLysVal                              420425430                                                                     GluAlaCysCysLysAsnLeuSerTyrValLysPheGlyMetTyrTyr                              435440445                                                                     GluAspLysAspLysAspAsnLysAsnGluThrAspLysGluLysGly                              450455460                                                                     LysGluLysProThrThrThrThrSerIleAsnThrTyrTyrGlnPhe                              465470475480                                                                  LeuLeuGlyLeuArgThrProLysAspGluIleProLysGluGlySer                              485490495                                                                     AlaLysTyrHisGlyAsnTrpPheGlyTyrIleSerAspGlyGluThr                              500505510                                                                     SerTyrSerAlaSerGlyAspLysGluArgSerLysAsnAlaValAla                              515520525                                                                     GluPheAspValSerPheAlaAsnLysThrLeuThrGlyGluLeuLys                              530535540                                                                     ArgHisAspAsnGlyAsnThrValPheLysIleAsnAlaGluLeuAsn                              545550555560                                                                  GlySerAsnAspPheThrGlyThrAlaThrAlaThrAsnPheValIle                              565570575                                                                     AspGlyAsnAsnSerGlnThrSerAsnAlaLysIleAsnIleThrThr                              580585590                                                                     LysValAsnGlyAlaPheTyrGlyProLysAlaSerGluLeuGlyGly                              595600605                                                                     TyrPheThrTyrAsnGlyLysAsnProThrAlaThrAsnSerGluSer                              610615620                                                                     SerSerThrValProSerProProAsnSerProAsnAlaSerAlaAla                              625630635640                                                                  ValValPheGlyAlaLysLysGlnValGluThrThrAsnLys                                    645650                                                                        (2) INFORMATION FOR SEQ ID NO:13:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                      AlaGluThrGlnSerIleLysAspThrLysGluAlaIleSerSerGlu                              151015                                                                        ValAspThrGlnSerThrGluAspSerGluLeuGluThrIleSerVal                              202530                                                                        ThrAlaGluLys                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:14:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                      SerValThrAlaGluLysValArgAspArgLysAspAsnGluValThr                              151015                                                                        GlyLeuGlyLysIleIleLysThrSerGluSerIleSerArgGluGln                              202530                                                                        ValLeuAsnIle                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:15:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                      SerArgGluGlnValLeuAsnIleArgAspLeuThrArgTyrAspPro                              151015                                                                        GlyIleSerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSer                              202530                                                                        IleArgGlyMet                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:16:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                      GlyTyrSerIleArgGlyMetAspArgAsnArgValAlaLeuLeuVal                              151015                                                                        AspGlyLeuProGlnThrGlnSerTyrValValGlnSerProLeuVal                              202530                                                                        AlaArgSerGly                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:17:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                      ProLeuValAlaArgSerGlyTyrGlyThrGlyAlaIleAsnGluIle                              151015                                                                        GluTyrGluAsnValLysAlaValGluIleSerLysGlyGlySerSer                              202530                                                                        SerGluTyrGly                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:18:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                      SerSerSerGluTyrGlyAsnGlyAlaLeuAlaGlySerValThrPhe                              151015                                                                        GlnSerLysSerAlaAlaAspIleLeuGluGlyAspLysSerTrpGly                              202530                                                                        IleGlnThrLys                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:19:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                      GlyIleGlnThrLysAsnAlaTyrSerSerLysAsnLysGlyPheThr                              151015                                                                        HisSerLeuAlaValAlaGlyLysGlnGlyGlyPheGluGlyValAla                              202530                                                                        IleTyrThrHis                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:20:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                      GlyValAlaIleTyrThrHisArgAsnSerIleGluThrGlnValHis                              151015                                                                        LysAspAlaLeuLysGlyValGlnSerTyrAspArgPheIleAlaThr                              202530                                                                        ThrGluAspGln                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:21:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                      IleAlaThrThrGluAspGlnSerAlaTyrPheValMetGlnAspGlu                              151015                                                                        CysLeuAspGlyTyrAspLysCysLysThrSerProLysArgProAla                              202530                                                                        ThrLeuSerThr                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:22:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                      ProAlaThrLeuSerThrGlnArgGluThrValSerValSerAspTyr                              151015                                                                        ThrGlyAlaAsnArgIleLysProAsnProMetLysTyrGluSerGln                              202530                                                                        SerTrpPheLeu                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:23:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                      TyrGluSerGlnSerTrpPheLeuArgGlyGlyTyrHisPheSerGlu                              151015                                                                        GlnHisTyrIleGlyGlyIlePheGluPheThrGlnGlnLysPheAsp                              202530                                                                        IleArgAspMet                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:24:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                      LysPheAspIleArgAspMetThrPheProAlaTyrLeuArgProThr                              151015                                                                        GluAspLysAspLeuGlnSerArgProPheTyrProLysGlnAspTyr                              202530                                                                        GlyAlaTyrGln                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:25:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                      AspTyrGlyAlaTyrGlnHisIleGlyAspGlyArgGlyValLysTyr                              151015                                                                        AlaSerGlyLeuTyrPheAspGluHisHisArgLysGlnArgValGly                              202530                                                                        IleGluTyrIle                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:26:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                      GlyIleGluTyrIleTyrGluAsnLysAsnLysAlaGlyIleIleAsp                              151015                                                                        LysAlaValLeuSerAlaAsnGlnGlnAsnIleIleLeuAspSerTyr                              202530                                                                        MetArgHisThr                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:27:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                      AspSerTyrMetArgHisThrHisCysSerLeuTyrProAsnProSer                              151015                                                                        LysAsnCysArgProThrLeuAspLysProTyrSerTyrTyrHisSer                              202530                                                                        AspArgAsnVal                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:28:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                      SerAspArgAsnValTyrLysGluLysHisAsnMetLeuGlnLeuAsn                              151015                                                                        LeuGluLysLysIleGlnGlnAsnTrpLeuThrHisGlnIleAlaPhe                              202530                                                                        AsnLeuGlyPhe                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:29:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                      ThrHisGlnIleAlaPheAsnLeuGlyPheAspAspPheThrSerAla                              151015                                                                        LeuGlnHisLysAspTyrLeuThrArgArgValIleAlaThrAlaSer                              202530                                                                        SerIleSerGlu                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:30:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 37 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                      ThrAlaSerSerIleSerGluLysArgGlyGluAlaArgArgAsnGly                              151015                                                                        LeuGlnSerSerProTyrLeuTyrProThrProLysAlaGluLeuVal                              202530                                                                        GlyGlyAspLeuCys                                                               35                                                                            (2) INFORMATION FOR SEQ ID NO:31:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                      LeuValGlyGlyAspLeuCysAsnTyrGlnGlyLysSerSerAsnTyr                              151015                                                                        SerAspCysLysValArgLeuIleLysGlyLysAsnTyrTyrPheAla                              202530                                                                        AlaArgAsnAsn                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:32:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                      PheAlaAlaArgAsnAsnMetAlaLeuGlyLysTyrValAspLeuGly                              151015                                                                        LeuGlyMetArgTyrAspValSerArgThrLysAlaAsnGluSerThr                              202530                                                                        IleSerValGly                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:33:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                      SerThrIleSerValGlyLysPheLysAsnPheSerTrpAsnThrGly                              151015                                                                        IleValIleLysProThrGluTrpLeuAspLeuSerTyrArgLeuSer                              202530                                                                        ThrGlyPheArg                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:34:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                      LeuSerThrGlyPheArgAsnProSerPheAlaGluMetTyrGlyTrp                              151015                                                                        ArgTyrGlyGlyLysAspThrAspValTyrIleGlyLysPheLysPro                              202530                                                                        GluThrSerArg                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:35:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                      LysProGluThrSerArgAsnGlnGluPheGlyLeuAlaLeuLysGly                              151015                                                                        AspPheGlyAsnIleGluIleSerHisPheSerAsnAlaTyrArgAsn                              202530                                                                        LeuIleAlaPhe                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:36:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                      TyrArgAsnLeuIleAlaPheAlaGluGluLeuSerLysAsnGlyThr                              151015                                                                        ThrGlyLysGlyAsnTyrGlyTyrHisAsnAlaGlnAsnAlaLysLeu                              202530                                                                        ValGlyValAsn                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:37:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                      AlaLysLeuValGlyValAsnIleThrAlaGlnLeuAspPheAsnGly                              151015                                                                        LeuTrpLysArgIleProTyrGlyTrpTyrAlaThrPheAlaTyrAsn                              202530                                                                        ArgValLysVal                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:38:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                      AlaTyrAsnArgValLysValLysAspGlnLysIleAsnAlaGlyLeu                              151015                                                                        AlaSerValSerSerTyrLeuPheAspAlaIleGlnProSerArgTyr                              202530                                                                        IleIleGlyLeu                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:39:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                      SerArgTyrIleIleGlyLeuAspTyrAspHisProSerAsnThrTrp                              151015                                                                        GlyIleLysThrMetPheThrGlnSerLysAlaLysSerGlnAsnGlu                              202530                                                                        LeuLeuGlyLys                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:40:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                      AsnGluLeuLeuGlyLysArgAlaLeuGlyAsnAsnSerArgAsnVal                              151015                                                                        LysSerThrArgLysLeuThrArgAlaTrpHisIleLeuAspValSer                              202530                                                                        GlyTyrTyrMet                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:41:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 30 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                      SerGlyTyrTyrMetValAsnArgSerIleLeuPheArgLeuGlyVal                              151015                                                                        TyrAsnLeuLeuAsnTyrArgTyrValThrTrpGluAlaVal                                    202530                                                                        (2) INFORMATION FOR SEQ ID NO:42:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                      LeuLeuAsnTyrArgTyrValThrTrpGluAlaValArgGlnThrAla                              151015                                                                        GlnGlyAlaGluPheAspIle                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO:43:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                      AspAsnGluValThrGlyLeuGlyLys                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO:44:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                      GluGlnValLeuAsnIleArgAspLeuThrArgTyrAspProGlyIle                              151015                                                                        (2) INFORMATION FOR SEQ ID NO:45:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                      GluGlnValLeuAsnIleArgAspLeuThrArgTyrAspProGlyIle                              151015                                                                        SerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSerIleArg                              202530                                                                        GlyMetAsp                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:46:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 19 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                      GlyAlaIleAsnGluIleGluTyrGluAsnValLysAlaValGluIle                              151015                                                                        SerLysGly                                                                     (2) INFORMATION FOR SEQ ID NO:47:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                      GlyAlaLeuAlaGlySerVal                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:48:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                      AlaGluThrGlnSerIleLysAspThrLysGluAlaIleSerCys                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO:49:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                      CysSerGlyGlyGlySerPheAspValAspAsnValSerAsn                                    1510                                                                          (2) INFORMATION FOR SEQ ID NO:50:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 31 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                      LeuGluGlyGlyPheTyrGlyProLysGlyGluGluLeuGlyPheArg                              151015                                                                        PheLeuAlaGlyAspLysLysValPheGlyValPheSerAlaLys                                 202530                                                                        (2) INFORMATION FOR SEQ ID NO:51:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                      ThrValGlyLysLysThrTyrGlnValGluAlaCysCysSerAsnLeu                              151015                                                                        SerTyrValLysPheGlyMet                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO:52:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                      AlaThrValLysGlyAlaPheTyrGlyProLysAlaSerGluLeuGly                              151015                                                                        GlyTyrPheThrTyrAsnGly                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO:53:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                      MetLysLeuAlaAlaLeuAsnLeuPheAspArgAsnLysProSerLeu                              151015                                                                        LeuAsnGluAspSerTyrMetIlePheSerSerArgSerThrIleGlu                              202530                                                                        GluAspVal                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:54:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                      SerThrIleGluGluAspValLysAsnAspAsnGlnAsnGlyGluHis                              151015                                                                        ProIleAspSerIleValAspProArgAlaProAsnSerAsnGluAsn                              202530                                                                        ArgHisGly                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:55:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                      SerAsnGluAsnArgHisGlyGlnLysTyrValTyrSerGlyLeuTyr                              151015                                                                        TyrIleGlnSerTrpSerLeuArgAspLeuProAsnLysLysPheTyr                              202530                                                                        SerGlyTyr                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:56:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                      LysLysPheTyrSerGlyTyrTyrGlyTyrAlaTyrTyrPheGlyAsn                              151015                                                                        ThrThrAlaSerAlaLeuProValGlyGlyValAlaThrTyrLysGly                              202530                                                                        ThrTrpSer                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:57:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                      ThrTyrLysGlyThrTrpSerPheIleThrAlaAlaGluAsnGlyLys                              151015                                                                        AsnTyrGluLeuLeuArgAsnSerGlyGlyGlyGlnAlaTyrSerArg                              202530                                                                        ArgSerAla                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:58:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                      AlaTyrSerArgArgSerAlaThrProGluAspIleAspLeuAspArg                              151015                                                                        LysThrGlyLeuThrSerGluPheThrValAsnPheGlyThrLysLys                              202530                                                                        LeuThrGly                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:59:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                      GlyThrLysLysLeuThrGlyGlyLeuTyrTyrAsnLeuArgGluThr                              151015                                                                        AspAlaAsnLysSerGlnAsnArgThrHisLysLeuTyrAspLeuGlu                              202530                                                                        AlaAspVal                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:60:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                      TyrAspLeuGluAlaAspValHisSerAsnArgPheArgGlyLysVal                              151015                                                                        LysProThrLysLysGluSerSerGluGluHisProPheThrSerGlu                              202530                                                                        GlyThrLeu                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:61:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                      PheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProGluGly                              151015                                                                        GlnGluLeuGlyGlyLysPheLeuAlaHisAspLysLysValLeuGly                              202530                                                                        ValPheSer                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:62:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                      LysValLeuGlyValPheSerAlaLysGluGlnGlnGluThrSerGlu                              151015                                                                        AsnLysLysLeuProLysGluThrLeuIleAspGlyLysLeuThrThr                              202530                                                                        PheLysThr                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:63:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                      LysLeuThrThrPheLysThrThrAsnAlaThrAlaAsnAlaThrThr                              151015                                                                        AspAlaThrThrSerThrThrAlaSerThrLysThrAspThrThrThr                              202530                                                                        AsnAlaThr                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:64:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                      AspThrThrThrAsnAlaThrAlaAsnThrGluAsnPheThrThrLys                              151015                                                                        AspIleProSerLeuGlyGluAlaAspTyrLeuLeuIleAspAsnTyr                              202530                                                                        ProValPro                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:65:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                      IleAspAsnTyrProValProLeuPheProGluSerGlyAspPheIle                              151015                                                                        SerSerLysHisHisThrValGlyLysLysThrTyrGlnValGluAla                              202530                                                                        CysCysSer                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:66:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 36 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                      CysSerAsnLeuSerTyrValLysPheGlyMetTyrTyrGluAlaPro                              151015                                                                        ProLysGluGluGluLysGluLysGluLysAspLysAspLysGluLys                              202530                                                                        GluLysGlnAla                                                                  35                                                                            (2) INFORMATION FOR SEQ ID NO:67:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                      LysGluLysAspLysAspLysGluLysGluLysGlnAlaThrThrSer                              151015                                                                        IleLysThrTyrTyrGlnPheLeuLeuGlyLeuArgThrProSerSer                              202530                                                                        GluIlePro                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:68:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                      ThrProSerSerGluIleProLysGluGlySerAlaLysTyrHisGly                              151015                                                                        AsnTrpPheGlyTyrIleSerAspGlyGluThrSerTyrSerAlaSer                              202530                                                                        GlyAspLys                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:69:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                      TyrSerAlaSerGlyAspLysGluArgSerLysAsnAlaValAlaGlu                              151015                                                                        PheAsnValAsnPheAlaGluLysThrLeuThrGlyGluLeuLysArg                              202530                                                                        HisAspThr                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:70:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                      GluLeuLysArgHisAspThrGlnAsnProValPheLysIleAsnAla                              151015                                                                        ThrPheGlnSerGlyLysAsnAspPheThrGlyThrAlaThrAlaLys                              202530                                                                        AspLeuAla                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:71:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                      AlaThrAlaLysAspLeuAlaIleAspGlyLysAsnThrGlnGlyThr                              151015                                                                        SerLysValAsnPheThrAlaThrValAsnGlyAlaPheTyrGlyPro                              202530                                                                        HisAlaThr                                                                     35                                                                            (2) INFORMATION FOR SEQ ID NO:72:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                      PheTyrGlyProHisAlaThrGluLeuGlyGlyTyrPheThrTyrAsn                              151015                                                                        GlyAsnAsnProThrAspLysAsnSerSer                                                2025                                                                          (2) INFORMATION FOR SEQ ID NO:73:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 31 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                      CysProThrAspLysAsnSerSerSerAsnSerGluLysAlaArgAla                              151015                                                                        AlaValValPheGlyAlaLysLysGlnGlnValGluThrThrLys                                 202530                                                                        (2) INFORMATION FOR SEQ ID NO:74:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                      LeuGluGlyGlyPheTyrGlyPro                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:75:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                      CysSerGlyGlyGlySerPheAsp                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:76:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acid                                                      (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                      TyrValTyrSerGlyLeu                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:77:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                      CysCysSerAsnLeuSerTyrValLysPheGly                                             1510                                                                          (2) INFORMATION FOR SEQ ID NO:78:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                      PheLeuLeuGlyHisArgThr                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:79:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                      GluPheAsnValAspPhe                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:80:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                      AsnAlaPheThrGlyThrAla                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:81:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                      ValAsnGlyAlaPheTyrGly                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:82:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                      GluLeuGlyGlyTyrPhe                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:83:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                      ValValPheGlyAlaArg                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:84:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                      ValValPheGlyAlaLys                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:85:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 7 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                      LeuGluGlyGlyPheTyrGly                                                         15                                                                            (2) INFORMATION FOR SEQ ID NO:86:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 103 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                      TATGGAAACTCAAAGTATAAAAGATACAAAAGAAGCTATATCATCTGAAGTGGACACTCA60                AAGTACAGAAGATTCAGAATTAGAAACTATCTCAGTCACTGCA103                                (2) INFORMATION FOR SEQ ID NO:87:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 97 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                      ACCTTTGAGTTTCATATTTTCTATGTTTTCTTCGATATAGTAGACTTCACCTGTGAGTTT60                CATGTCTTCTAAGTCTTAATCTTTGATAGAGTCAGTG97                                       (2) INFORMATION FOR SEQ ID NO:88:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 115 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                      TATGAAAGCTACTAAACTGGTTCTGGGTGCTGTTATCCTGGGTTCCACTCTGCTGGCTGG60                TTGTAGCGGAGGTGGTTGTTTTGATGTAGATAACGTCTCTAATACCCCCTCTTCT115                    (2) INFORMATION FOR SEQ ID NO:89:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 116 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                      ACTTTCGATGATTTGACCAAGACCCACGACAATAGGACCCAAGGTGAGACGACCGACCAA60                CATCGCCTCCACCAACAAAACTACATCTATTGCAGAGATTATGGGGGAGAAGATTT116                   (2) INFORMATION FOR SEQ ID NO:90:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 109 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                      TATGCGATATCTGGCAACATTGTTGTTATCTCTGGCGGTGTTAATCACCGCTGGTTGTAG60                CGGAGGTGGTTCTTTTGATGTAGATAACGTCTCTAATACCCCCTCTTCT109                          (2) INFORMATION FOR SEQ ID NO:91:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 110 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                      ACGCTATAGACCGTTGTAACAACAATAGAGACCGCCACAATTAGTGGCGACCAACATCGC60                CTCCACCAAGAAAACTACATCTATTGCAGAGATTATGGGGGAGAAGATTT110                         (2) INFORMATION FOR SEQ ID NO:92:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 117 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                      TATGCAACTGAACAAAGTGCTGAAAGGGCTGATGATTGCTCTGCCTGTTATGGCAATGCT60                GGTTGTAGCGGAGGTGGTTCTTTTGATGTAGATAACGTCTCTAATACCCCCTCTTCT117                  (2) INFORMATION FOR SEQ ID NO:93:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 119 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                      ACGTTGACTTGTTTCACGACTTTCCCGACTACTAACGAGACGGACAATACCGTTAACGAC60                CAACATCGCCTCCACCAAGAAAACTACATCTATTGCAGAGATTATGGGGGAGAAGATTT119                (2) INFORMATION FOR SEQ ID NO:94:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 908 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                      MetGlnGlnGlnHisLeuPheArgLeuAsnIleLeuCysLeuSerLeu                              151015                                                                        MetThrAlaLeuProValTyrAlaGluAsnValGlnAlaGluGlnAla                              202530                                                                        GlnGluLysGlnLeuAspThrIleGlnValLysAlaLysLysGlnLys                              354045                                                                        ThrArgArgAspAsnGluValThrGlyLeuGlyLysLeuValLysSer                              505560                                                                        SerAspThrLeuSerLysGluGlnValLeuAsnIleArgAspLeuThr                              65707580                                                                      ArgTyrAspProGlyIleAlaValValGluGlnGlyArgGlyAlaSer                              859095                                                                        SerGlyTyrSerIleArgGlyMetAspLysAsnArgValSerLeuThr                              100105110                                                                     ValAspGlyValSerGlnIleGlnSerTyrThrAlaGlnAlaAlaLeu                              115120125                                                                     GlyGlyThrArgThrAlaGlySerSerGlyAlaIleAsnGluIleGlu                              130135140                                                                     TyrGluAsnValLysAlaValGluIleSerLysGlySerAsnSerSer                              145150155160                                                                  GluTyrGlyAsnGlyAlaLeuAlaGlySerValAlaPheGlnThrLys                              165170175                                                                     ThrAlaAlaAspIleIleGlyGluGlyLysGlnTrpGlyIleGlnSer                              180185190                                                                     LysThrAlaTyrSerGlyLysAspHisAlaLeuThrGlnSerLeuAla                              195200205                                                                     LeuAlaGlyArgSerGlyGlyAlaGluAlaLeuLeuIleTyrThrLys                              210215220                                                                     ArgArgGlyArgGluIleHisAlaHisLysAspAlaGlyLysGlyVal                              225230235240                                                                  GlnSerPheAsnArgLeuValLeuAspGluAspLysLysGluGlyGly                              245250255                                                                     SerGlnTyrArgTyrPheIleValGluGluGluCysHisAsnGlyTyr                              260265270                                                                     AlaAlaCysLysAsnLysLeuLysGluAspAlaSerValLysAspGlu                              275280285                                                                     ArgLysThrValSerThrGlnAspTyrThrGlySerAsnArgLeuLeu                              290295300                                                                     AlaAsnProLeuGluTyrGlySerGlnSerTrpLeuPheArgProGly                              305310315320                                                                  TrpHisLeuAspAsnArgHisTyrValGlyAlaValLeuGluArgThr                              325330335                                                                     GlnGlnThrPheAspThrArgAspMetThrValProAlaTyrPheThr                              340345350                                                                     SerGluAspTyrValProGlySerLeuLysGlyLeuGlyLysTyrSer                              355360365                                                                     GlyAspAsnLysAlaGluArgLeuPheValGlnGlyGluGlySerThr                              370375380                                                                     LeuGlnGlyIleGlyTyrGlyThrGlyValPheTyrAspGluArgHis                              385390395400                                                                  ThrLysAsnArgTyrGlyValGluTyrValTyrHisAsnAlaAspLys                              405410415                                                                     AspThrTrpAlaAspTyrAlaArgLeuSerTyrAspArgGlnGlyIle                              420425430                                                                     AspLeuAspAsnArgLeuGlnGlnThrHisCysSerHisAspGlySer                              435440445                                                                     AspLysAsnCysArgProAspGlyAsnLysProTyrSerPheTyrLys                              450455460                                                                     SerAspArgMetIleTyrGluGluSerArgAsnLeuPheGlnAlaVal                              465470475480                                                                  PheLysLysAlaPheAspThrAlaLysIleArgHisAsnLeuSerIle                              485490495                                                                     AsnLeuGlyTyrAspArgPheLysSerGlnLeuSerHisSerAspTyr                              500505510                                                                     TyrLeuGlnAsnAlaValGlnAlaTyrAspLeuIleThrProLysLys                              515520525                                                                     ProProPheProAsnGlySerLysAspAsnProTyrArgValSerIle                              530535540                                                                     GlyLysThrThrValAsnThrSerProIleCysArgPheGlyAsnAsn                              545550555560                                                                  ThrTyrThrAspCysThrProArgAsnIleGlyGlyAsnGlyTyrTyr                              565570575                                                                     AlaAlaValGlnAspAsnValArgLeuGlyArgTrpAlaAspValGly                              580585590                                                                     AlaGlyIleArgTyrAspTyrArgSerThrHisSerGluAspLysSer                              595600605                                                                     ValSerThrGlyThrHisArgAsnLeuSerTrpAsnAlaGlyValVal                              610615620                                                                     LeuLysProPheThrTrpMetAspLeuThrTyrArgAlaSerThrGly                              625630635640                                                                  PheArgLeuProSerPheAlaGluMetTyrGlyTrpArgAlaGlyGlu                              645650655                                                                     SerLeuLysThrLeuAspLeuLysProGluLysSerPheAsnArgGlu                              660665670                                                                     AlaGlyIleValPheLysGlyAspPheGlyAsnLeuGluAlaSerTyr                              675680685                                                                     PheAsnAsnAlaTyrArgAspLeuIleAlaPheGlyTyrGluThrArg                              690695700                                                                     ThrGlnAsnGlyGlnThrSerAlaSerGlyAspProGlyTyrArgAsn                              705710715720                                                                  AlaGlnAsnAlaArgIleAlaGlyIleAsnIleLeuGlyLysIleAsp                              725730735                                                                     TrpHisGlyValTrpGlyGlyLeuProAspGlyLeuTyrSerThrLeu                              740745750                                                                     AlaTyrAsnArgIleLysValLysAspAlaAspIleArgAlaAspArg                              755760765                                                                     ThrPheValThrSerTyrLeuPheAspAlaValGlnProSerArgTyr                              770775780                                                                     ValLeuGlyLeuGlyTyrAspHisProAspGlyIleTrpGlyIleAsn                              785790795800                                                                  ThrMetPheThrTyrSerLysAlaLysSerValAspGluLeuLeuGly                              805810815                                                                     SerGlnAlaLeuLeuAsnGlyAsnAlaAsnAlaLysLysAlaAlaSer                              820825830                                                                     ArgArgThrArgProTrpTyrValThrAspValSerGlyTyrTyrAsn                              835840845                                                                     IleLysLysHisLeuThrLeuArgAlaGlyValTyrAsnLeuLeuAsn                              850855860                                                                     TyrArgTyrValThrTrpGluAsnValArgGlnThrAlaGlyGlyAla                              865870875880                                                                  ValAsnGlnHisLysAsnValGlyValTyrAsnArgTyrAlaAlaPro                              885890895                                                                     GlyArgAsnTyrThrPheSerLeuGluMetLysPhe                                          900905                                                                        (2) INFORMATION FOR SEQ ID NO:95:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 911 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                      MetGlnGlnGlnHisLeuPheArgLeuAsnIleLeuCysLeuSerLeu                              151015                                                                        MetThrAlaLeuProAlaTyrAlaGluAsnValGlnAlaGlyGlnAla                              202530                                                                        GlnGluLysGlnLeuAspThrIleGlnValLysAlaLysLysGlnLys                              354045                                                                        ThrArgArgAspAsnGluValThrGlyLeuGlyLysLeuValLysThr                              505560                                                                        AlaAspThrLeuSerLysGluGlnValLeuAspIleArgAspLeuThr                              65707580                                                                      ArgTyrAspProGlyIleAlaValValGluGlnGlyArgGlyAlaSer                              859095                                                                        SerGlyTyrSerIleArgGlyMetAspLysAsnArgValSerLeuThr                              100105110                                                                     ValAspGlyLeuAlaGlnIleGlnSerTyrThrAlaGlnAlaAlaLeu                              115120125                                                                     GlyGlyThrArgThrAlaGlySerSerGlyAlaIleAsnGluIleGlu                              130135140                                                                     TyrGluAsnValLysAlaValGluIleSerLysGlySerAsnSerVal                              145150155160                                                                  GluGlnGlySerGlyAlaLeuAlaGlySerValAlaPheGlnThrLys                              165170175                                                                     ThrAlaAspAspValIleGlyGluGlyArgGlnTrpGlyIleGlnSer                              180185190                                                                     LysThrAlaTyrSerGlyLysAsnArgGlyLeuThrGlnSerIleAla                              195200205                                                                     LeuAlaGlyArgIleGlyGlyAlaGluAlaLeuLeuIleHisThrGly                              210215220                                                                     ArgArgAlaGlyGluIleArgAlaHisGluAspAlaGlyArgGlyVal                              225230235240                                                                  GlnSerPheAsnArgLeuValProValGluAspSerSerGluTyrAla                              245250255                                                                     TyrPheIleValGluAspGluCysGluGlyLysAsnTyrGluThrCys                              260265270                                                                     LysSerLysProLysLysAspValValGlyLysAspGluArgGlnThr                              275280285                                                                     ValSerThrArgAspTyrThrGlyProAsnArgPheLeuAlaAspPro                              290295300                                                                     LeuSerTyrGluSerArgSerTrpLeuPheArgProGlyPheArgPhe                              305310315320                                                                  GluAsnLysArgHisTyrIleGlyGlyIleLeuGluHisThrGlnGln                              325330335                                                                     ThrPheAspThrArgAspMetThrValProAlaPheLeuThrLysAla                              340345350                                                                     ValPheAspAlaAsnSerLysGlnAlaGlySerLeuProGlyAsnGly                              355360365                                                                     LysTyrAlaGlyAsnHisLysTyrGlyGlyLeuPheThrAsnGlyGlu                              370375380                                                                     AsnGlyAlaLeuValGlyAlaGluTyrGlyThrGlyValPheTyrAsp                              385390395400                                                                  GluThrHisThrLysSerArgTyrGlyLeuGluTyrValTyrThrAsn                              405410415                                                                     AlaAspLysAspThrTrpAlaAspTyrAlaArgLeuSerTyrAspArg                              420425430                                                                     GlnGlyIleGlyLeuAspAsnHisPheGlnGlnThrHisCysSerAla                              435440445                                                                     AspGlySerAspLysTyrCysArgProSerAlaAspLysProPheSer                              450455460                                                                     TyrTyrLysSerAspArgValIleTyrGlyGluSerHisArgLeuLeu                              465470475480                                                                  GlnAlaAlaPheLysLysSerPheAspThrAlaLysIleArgHisAsn                              485490495                                                                     LeuSerValAsnLeuGlyPheAspArgPheAspSerAsnLeuArgHis                              500505510                                                                     GlnAspTyrTyrTyrGlnHisAlaAsnArgAlaTyrSerSerLysThr                              515520525                                                                     ProProLysThrAlaAsnProAsnGlyAspLysSerLysProTyrTrp                              530535540                                                                     ValSerIleGlyGlyGlyAsnValValThrGlyGlnIleCysLeuPhe                              545550555560                                                                  GlyAsnAsnThrTyrThrAspCysThrProArgSerIleAsnGlyLys                              565570575                                                                     SerTyrTyrAlaAlaValArgAspAsnValArgLeuGlyArgTrpAla                              580585590                                                                     AspValGlyAlaGlyLeuArgTyrAspTyrArgSerThrHisSerAsp                              595600605                                                                     AspGlySerValSerThrGlyThrHisArgThrLeuSerTrpAsnAla                              610615620                                                                     GlyIleValLeuLysProAlaAspTrpLeuAspLeuThrTyrArgThr                              625630635640                                                                  SerThrGlyPheArgLeuProSerPheAlaGluMetTyrGlyTrpArg                              645650655                                                                     SerGlyValGlnSerLysAlaValLysIleAspProGluLysSerPhe                              660665670                                                                     AsnLysGluAlaGlyIleValPheLysGlyAspPheGlyAsnLeuGlu                              675680685                                                                     AlaSerTrpPheAsnAsnAlaTyrArgAspLeuIleValArgGlyTyr                              690695700                                                                     GluAlaGlnIleLysAsnGlyLysGluGluAlaLysGlyAspProAla                              705710715720                                                                  TyrLeuAsnAlaGlnSerAlaArgIleThrGlyIleAsnIleLeuGly                              725730735                                                                     LysIleAspTrpAsnGlyValTrpAspLysLeuProGluGlyTrpTyr                              740745750                                                                     SerThrPheAlaTyrAsnArgValHisValArgAspIleLysLysArg                              755760765                                                                     AlaAspArgThrAspIleGlnSerHisLeuPheAspAlaIleGlnPro                              770775780                                                                     SerArgTyrValValGlyLeuGlyTyrAspGlnProGluGlyLysTrp                              785790795800                                                                  GlyValAsnGlyMetLeuThrTyrSerLysAlaLysGluIleThrGlu                              805810815                                                                     LeuLeuGlySerArgAlaLeuLeuAsnGlyAsnSerArgAsnThrLys                              820825830                                                                     AlaThrAlaArgArgThrArgProTrpTyrIleValAspValSerGly                              835840845                                                                     TyrTyrThrIleLysLysHisPheThrLeuArgAlaGlyValTyrAsn                              850855860                                                                     LeuLeuAsnTyrArgTyrValThrTrpGluAsnValArgGlnThrAla                              865870875880                                                                  GlyGlyAlaValAsnGlnHisLysAsnValGlyValTyrAsnArgTyr                              885890895                                                                     AlaAlaProGlyArgAsnTyrThrPheSerLeuGluMetLysPhe                                 900905910                                                                     (2) INFORMATION FOR SEQ ID NO:96:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 915 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                      MetGlnGlnGlnHisLeuPheArgLeuAsnIleLeuCysLeuSerLeu                              151015                                                                        MetThrAlaLeuProAlaTyrAlaGluAsnValGlnAlaGlyGlnAla                              202530                                                                        GlnGluLysGlnLeuAspThrIleGlnValLysAlaLysLysGlnLys                              354045                                                                        ThrArgArgAspAsnGluValThrGlyLeuGlyLysLeuValLysThr                              505560                                                                        AlaAspThrLeuSerLysGluGlnValLeuAspIleArgAspLeuThr                              65707580                                                                      ArgTyrAspProGlyIleAlaValValGluGlnGlyArgGlyAlaSer                              859095                                                                        SerGlyTyrSerIleArgGlyMetAspLysAsnArgValSerLeuThr                              100105110                                                                     ValAspGlyLeuAlaGlnIleGlnSerTyrThrAlaGlnAlaAlaLeu                              115120125                                                                     GlyGlyThrArgThrAlaGlySerSerGlyAlaIleAsnGluIleGlu                              130135140                                                                     TyrGluAsnValLysAlaValGluIleSerLysGlySerAsnSerVal                              145150155160                                                                  GluGlnGlySerGlyAlaLeuAlaGlySerValAlaPheGlnThrLys                              165170175                                                                     ThrAlaAspAspValIleGlyGluGlyArgGlnTrpGlyIleGlnSer                              180185190                                                                     LysThrAlaTyrSerGlyLysAsnArgGlyLeuThrGlnSerIleAla                              195200205                                                                     LeuAlaGlyArgIleGlyGlyAlaGluAlaLeuLeuIleArgThrGly                              210215220                                                                     ArgHisAlaGlyGluIleArgAlaHisGluAlaAlaGlyArgGlyVal                              225230235240                                                                  GlnSerPheAsnArgLeuAlaProValAspAspGlySerLysTyrAla                              245250255                                                                     TyrPheIleValGluGluGluCysLysAsnGlyGlyHisGluLysCys                              260265270                                                                     LysAlaAsnProLysLysAspValValGlyGluAspLysArgGlnThr                              275280285                                                                     ValSerThrArgAspTyrThrGlyProAsnArgPheLeuAlaAspPro                              290295300                                                                     LeuSerTyrGluSerArgSerTrpLeuPheArgProGlyPheArgPhe                              305310315320                                                                  GluAsnLysArgHisTyrIleGlyGlyIleLeuGluArgThrGlnGln                              325330335                                                                     ThrPheAspThrArgAspMetThrValProAlaPheLeuThrLysAla                              340345350                                                                     ValPheAspAlaAsnGlnLysGlnAlaGlySerLeuArgGlyAsnGly                              355360365                                                                     LysTyrAlaGlyAsnHisLysTyrGlyGlyLeuPheThrSerGlyGlu                              370375380                                                                     AsnAsnAlaProValGlyAlaGluTyrGlyThrGlyValPheTyrAsp                              385390395400                                                                  GluThrHisThrLysSerArgTyrGlyLeuGluTyrValTyrThrAsn                              405410415                                                                     AlaAspLysAspThrTrpAlaAspTyrAlaArgLeuSerTyrAspArg                              420425430                                                                     GlnGlyIleGlyLeuAspAsnHisPheGlnGlnThrHisCysSerAla                              435440445                                                                     AspGlySerAspLysTyrCysArgProSerAlaAspLysProPheSer                              450455460                                                                     TyrTyrLysSerAspArgValIleTyrGlyGluSerHisLysLeuLeu                              465470475480                                                                  GlnAlaAlaPheLysLysSerPheAspThrAlaLysIleArgHisAsn                              485490495                                                                     LeuSerValAsnLeuGlyTyrAspArgPheGlySerAsnLeuArgHis                              500505510                                                                     GlnAspTyrTyrTyrGlnSerAlaAsnArgAlaTyrSerLeuLysThr                              515520525                                                                     ProProGlnAsnAsnGlyLysLysThrSerProAsnGlyArgGluLys                              530535540                                                                     AsnProTyrTrpValSerIleGlyArgGlyAsnValValThrArgGln                              545550555560                                                                  IleCysLeuPheGlyAsnAsnThrTyrThrAspCysThrProArgSer                              565570575                                                                     IleAsnGlyLysSerTyrTyrAlaAlaValArgAspAsnValArgLeu                              580585590                                                                     GlyArgTrpAlaAspValGlyAlaGlyLeuArgTyrAspTyrArgSer                              595600605                                                                     ThrHisSerAspAspGlySerValSerThrGlyThrHisArgThrLeu                              610615620                                                                     SerTrpAsnAlaGlyIleValLeuLysProAlaAspTrpLeuAspLeu                              625630635640                                                                  ThrTyrArgThrSerThrGlyPheArgLeuProSerPheAlaGluMet                              645650655                                                                     TyrGlyTrpArgSerGlyAspLysIleLysAlaValLysIleAspPro                              660665670                                                                     GluLysSerPheAsnLysGluAlaGlyIleValPheLysGlyAspPhe                              675680685                                                                     GlyAsnLeuGluAlaSerTrpPheAsnAsnAlaTyrArgAspLeuIle                              690695700                                                                     ValArgGlyTyrGluAlaGlnIleLysAspGlyLysGluGlnValLys                              705710715720                                                                  GlyAsnProAlaTyrLeuAsnAlaGlnSerAlaArgIleThrGlyIle                              725730735                                                                     AsnIleLeuGlyLysIleAspTrpAsnGlyValTrpAspLysLeuPro                              740745750                                                                     GluGlyTrpTyrSerThrPheAlaTyrAsnArgValArgValArgAsp                              755760765                                                                     IleLysLysArgAlaAspArgThrAspIleGlnSerHisLeuPheAsp                              770775780                                                                     AlaIleGlnProSerArgTyrValValGlySerGlyTyrAspGlnPro                              785790795800                                                                  GluGlyLysTrpGlyValAsnGlyMetLeuThrTyrSerLysAlaLys                              805810815                                                                     GluIleThrGluLeuLeuGlySerArgAlaLeuLeuAsnGlyAsnSer                              820825830                                                                     ArgAsnThrLysAlaThrAlaArgArgThrArgProTrpTyrIleVal                              835840845                                                                     AspValSerGlyTyrTyrThrValLysLysHisPheThrLeuArgAla                              850855860                                                                     GlyValTyrAsnLeuLeuAsnHisArgTyrValThrTrpGluAsnVal                              865870875880                                                                  ArgGlnThrAlaAlaGlyAlaValAsnGlnHisLysAsnValGlyVal                              885890895                                                                     TyrAsnArgTyrAlaAlaProGlyArgAsnTyrThrPheSerLeuGlu                              900905910                                                                     MetLysPhe                                                                     915                                                                           (2) INFORMATION FOR SEQ ID NO:97:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 598 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                      MetAsnAsnProLeuValAsnGlnAlaAlaMetValLeuProValPhe                              151015                                                                        LeuLeuSerAlaCysLeuGlyGlyGlyGlySerPheAspLeuAspSer                              202530                                                                        ValGluThrValGlnAspMetHisSerLysProLysTyrGluAspGlu                              354045                                                                        LysSerGlnProGluSerGlnGlnAspValSerGluAsnSerGlyAla                              505560                                                                        AlaTyrGlyPheAlaValLysLeuProArgArgAsnAlaHisPheAsn                              65707580                                                                      ProLysTyrLysGluLysHisLysProLeuGlySerMetAspTrpLys                              859095                                                                        LysLeuGlnArgGlyGluProAsnSerPheSerGluArgAspGluLeu                              100105110                                                                     GluLysLysArgGlySerSerGluLeuIleGluSerLysTrpGluAsp                              115120125                                                                     GlyGlnSerArgValValGlyTyrThrAsnPheThrTyrValArgSer                              130135140                                                                     GlyTyrValTyrLeuAsnLysAsnAsnIleAspIleLysAsnAsnIle                              145150155160                                                                  ValLeuPheGlyProAspGlyTyrLeuTyrTyrLysGlyLysGluPro                              165170175                                                                     SerLysGluLeuProSerGluLysIleThrTyrLysGlyThrTrpAsp                              180185190                                                                     TyrValThrAspAlaMetGluLysGlnArgPheGluGlyLeuGlySer                              195200205                                                                     AlaAlaGlyGlyAspLysSerGlyAlaLeuSerAlaLeuGluGluGly                              210215220                                                                     ValLeuArgAsnGlnAlaGluAlaSerSerGlyHisThrAspPheGly                              225230235240                                                                  MetThrSerGluPheGluValAspPheSerAspLysThrIleLysGly                              245250255                                                                     ThrLeuTyrArgAsnAsnArgIleThrGlnAsnAsnSerGluAsnLys                              260265270                                                                     GlnIleLysThrThrArgTyrThrIleGlnAlaThrLeuHisGlyAsn                              275280285                                                                     ArgPheLysGlyLysAlaLeuAlaAlaAspLysGlyAlaThrAsnGly                              290295300                                                                     SerHisProPheIleSerAspSerAspSerLeuGluGlyGlyPheTyr                              305310315320                                                                  GlyProLysGlyGluGluLeuAlaGlyLysPheLeuSerAsnAspAsn                              325330335                                                                     LysValAlaAlaValPheGlyAlaLysGlnLysAspLysLysAspGly                              340345350                                                                     GluAsnAlaAlaGlyProAlaThrGluValIleAspAlaTyrArgIle                              355360365                                                                     ThrGlyGluGluPheLysLysGluGlnIleAspSerPheGlyAspVal                              370375380                                                                     LysLysLeuLeuValAspGlyValGluLeuSerLeuLeuProSerGlu                              385390395400                                                                  GlyAsnLysAlaAlaPheGlnHisGluIleGluGlnAsnGlyValLys                              405410415                                                                     AlaThrValCysCysSerAsnLeuAspTyrMetSerPheGlyLysLeu                              420425430                                                                     SerLysGluAsnLysAspAspMetPheLeuGlnGlyValArgThrPro                              435440445                                                                     ValSerAspValAlaAlaArgThrGluAlaAsnAlaLysTyrArgGly                              450455460                                                                     ThrTrpTyrGlyTyrIleAlaAsnGlyThrSerTrpSerGlyGluAla                              465470475480                                                                  SerAsnGlnGluGlyGlyAsnArgAlaGluPheAspValAspPheSer                              485490495                                                                     ThrLysLysIleSerGlyThrLeuThrAlaLysAspArgThrSerPro                              500505510                                                                     AlaPheThrIleThrAlaMetIleLysAspAsnGlyPheSerGlyVal                              515520525                                                                     AlaLysThrGlyGluAsnGlyPheAlaLeuAspProGlnAsnThrGly                              530535540                                                                     AsnSerHisTyrThrHisIleGluAlaThrValSerGlyGlyPheTyr                              545550555560                                                                  GlyLysAsnAlaIleGluMetGlyGlySerPheSerPheProGlyAsn                              565570575                                                                     AlaProGluGlyLysGlnGluLysAlaSerValValPheGlyAlaLys                              580585590                                                                     ArgGlnGlnLeuValGln                                                            595                                                                           (2) INFORMATION FOR SEQ ID NO:98:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 711 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                      MetAsnAsnProLeuValAsnGlnAlaAlaMetValLeuProValPhe                              151015                                                                        LeuLeuSerAlaCysLeuGlyGlyGlyGlySerPheAspLeuAspSer                              202530                                                                        ValAspThrGluAlaProArgProAlaProLysTyrGlnAspValSer                              354045                                                                        SerGluLysProGlnAlaGlnLysAspGlnGlyGlyTyrGlyPheAla                              505560                                                                        MetArgLeuLysArgArgAsnTrpTyrProGlyAlaGluGluSerGlu                              65707580                                                                      ValLysLeuAsnGluSerAspTrpGluAlaThrGlyLeuProThrLys                              859095                                                                        ProLysGluLeuProLysArgGlnLysSerValIleGluLysValGlu                              100105110                                                                     ThrAspGlyAspSerAspIleTyrSerSerProTyrLeuThrProSer                              115120125                                                                     AsnHisGlnAsnGlySerAlaGlyAsnGlyValAsnGlnProLysAsn                              130135140                                                                     GlnAlaThrGlyHisGluAsnPheGlnTyrValTyrSerGlyTrpPhe                              145150155160                                                                  TyrLysHisAlaAlaSerGluLysAspPheSerAsnLysLysIleLys                              165170175                                                                     SerGlyAspAspGlyTyrIlePheTyrHisGlyGluLysProSerArg                              180185190                                                                     GlnLeuProAlaSerGlyLysValIleTyrLysGlyValTrpHisPhe                              195200205                                                                     ValThrAspThrLysLysGlyGlnAspPheArgGluIleIleGlnPro                              210215220                                                                     SerLysLysGlnGlyAspArgTyrSerGlyPheSerGlyAspGlySer                              225230235240                                                                  GluGluTyrSerAsnLysAsnGluSerThrLeuLysAspAspHisGlu                              245250255                                                                     GlyTyrGlyPheThrSerAsnLeuGluValAspPheGlyAsnLysLys                              260265270                                                                     LeuThrGlyLysLeuIleArgAsnAsnAlaSerLeuAsnAsnAsnThr                              275280285                                                                     AsnAsnAspLysHisThrThrGlnTyrTyrSerLeuAspAlaGlnIle                              290295300                                                                     ThrGlyAsnArgPheAsnGlyThrAlaThrAlaThrAspLysLysGlu                              305310315320                                                                  AsnGluThrLysLeuHisProPheValSerAspSerSerSerLeuSer                              325330335                                                                     GlyGlyPhePheGlyProGlnGlyGluGluLeuGlyPheArgPheLeu                              340345350                                                                     SerAspAspGlnLysValAlaValValGlySerAlaLysThrLysAsp                              355360365                                                                     LysLeuGluAsnGlyAlaAlaAlaSerGlySerThrGlyAlaAlaAla                              370375380                                                                     SerGlyGlyAlaAlaGlyThrSerSerGluAsnSerLysLeuThrThr                              385390395400                                                                  ValLeuAspAlaValGluLeuThrLeuAsnAspLysLysIleLysAsn                              405410415                                                                     LeuAspAsnPheSerAsnAlaAlaGlnLeuValValAspGlyIleMet                              420425430                                                                     IleProLeuLeuProLysAspSerGluSerGlyAsnThrGlnAlaAsp                              435440445                                                                     LysGlyLysAsnGlyGlyThrGluPheThrArgLysPheGluHisThr                              450455460                                                                     ProGluSerAspLysLysAspAlaGlnAlaGlyThrGlnThrAsnGly                              465470475480                                                                  AlaGlnThrAlaSerAsnThrAlaGlyAspThrAsnGlyLysThrLys                              485490495                                                                     ThrTyrGluValGluValCysCysSerAsnLeuAsnTyrLeuLysTyr                              500505510                                                                     GlyMetLeuThrArgLysAsnSerLysSerAlaMetGlnAlaGlyGly                              515520525                                                                     AsnSerSerGlnAlaAspAlaLysThrGluGlnValGluGlnSerMet                              530535540                                                                     PheLeuGlnGlyGluArgThrAspGluLysGluIleProThrAspGln                              545550555560                                                                  AsnValValTyrArgGlySerTrpTyrGlyHisIleAlaAsnGlyThr                              565570575                                                                     SerTrpSerGlyAsnAlaSerAspLysGluGlyGlyAsnArgAlaGlu                              580585590                                                                     PheThrValAsnPheAlaAspLysLysIleThrGlyLysLeuThrAla                              595600605                                                                     GluAsnArgGlnAlaGlnThrPheThrIleGluGlyMetIleGlnGly                              610615620                                                                     AsnGlyPheGluGlyThrAlaLysThrAlaGluSerGlyPheAspLeu                              625630635640                                                                  AspGlnLysAsnThrThrArgThrProLysAlaTyrIleThrAspAla                              645650655                                                                     LysValLysGlyGlyPheTyrGlyProLysAlaGluGluLeuGlyGly                              660665670                                                                     TrpPheAlaTyrProGlyAspLysGlnThrGluLysAlaThrAlaThr                              675680685                                                                     SerSerAspGlyAsnSerAlaSerSerAlaThrValValPheGlyAla                              690695700                                                                     LysArgGlnGlnProValGln                                                         705710                                                                        (2) INFORMATION FOR SEQ ID NO:99:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 546 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                      MetHisPheLysLeuAsnProTyrAlaLeuAlaPheThrSerLeuPhe                              151015                                                                        LeuValAlaCysSerGlyGlyLysGlySerPheAspLeuGluAspVal                              202530                                                                        ArgProAsnLysThrThrGlyValSerLysGluGluTyrLysAspVal                              354045                                                                        GluThrAlaLysLysGluLysGluGlnLeuGlyGluLeuMetGluPro                              505560                                                                        AlaLeuGlyTyrValValLysValProValSerSerPheGluAsnLys                              65707580                                                                      LysValAspIleSerAspIleGluValIleThrAsnGlyAsnLeuAsp                              859095                                                                        AspValProTyrLysAlaAsnSerSerLysTyrAsnTyrProAspIle                              100105110                                                                     LysThrLysAspSerSerLeuGlnTyrValArgSerGlyTyrValIle                              115120125                                                                     AspGlyGluHisSerGlySerAsnGluLysGlyTyrValTyrTyrLys                              130135140                                                                     GlyAsnSerProAlaLysGluLeuProValAsnGlnLeuLeuThrTyr                              145150155160                                                                  ThrGlySerTrpAspPheThrSerAsnAlaAsnLeuAsnAsnGluGlu                              165170175                                                                     GlyArgProAsnTyrLeuAsnAspAspTyrTyrThrLysPheIleGly                              180185190                                                                     LysArgValGlyLeuValSerGlyAspAlaLysProAlaLysHisLys                              195200205                                                                     TyrThrSerGlnPheGluValAspPheAlaThrLysLysMetThrGly                              210215220                                                                     LysSerAspLysGluLysThrIleTyrThrValAsnAlaAspIleArg                              225230235240                                                                  GlyAsnArgPheThrGlyAlaAlaThrAlaSerAspLysAsnLysGly                              245250255                                                                     LysGlyGluSerTyrAsnPhePheSerAlaAspSerGlnSerLeuGlu                              260265270                                                                     GlyGlyPheTyrGlyProLysAlaGluGluMetAlaGlyLysPheVal                              275280285                                                                     AlaAsnAspLysSerLeuPheAlaValPheSerAlaLysHisAsnGly                              290295300                                                                     SerAsnValAsnThrValArgIleIleAspAlaSerLysIleAspLeu                              305310315320                                                                  ThrAsnPheSerIleSerGluLeuAsnAsnPheGlyAspAlaSerVal                              325330335                                                                     LeuIleIleAspGlyLysLysIleLysLeuAlaGlySerGlyPheThr                              340345350                                                                     AsnLysHisThrIleGluIleAsnGlyLysThrMetValAlaValAla                              355360365                                                                     CysCysSerAsnLeuGluTyrMetLysPheGlyGlnLeuTrpGlnGln                              370375380                                                                     AlaGluGlyGlyLysProGluAsnAsnSerLeuPheLeuGlnGlyGlu                              385390395400                                                                  ArgThrAlaThrAspLysMetProLysGlyGlyAsnTyrLysTyrIle                              405410415                                                                     GlyThrTrpAspAlaGlnValSerLysGluAsnAsnTrpValAlaThr                              420425430                                                                     AlaAspAspAspArgLysAlaGlyTyrArgThrGluPheAspValAsp                              435440445                                                                     PheGlyAsnLysAsnLeuSerGlyLysLeuPheAspLysAsnGlyVal                              450455460                                                                     AsnProValPheThrValAspAlaLysIleAspGlyAsnGlyPheThr                              465470475480                                                                  GlyLysAlaLysThrSerAspGluGlyPheAlaLeuAspSerGlySer                              485490495                                                                     SerArgTyrGluAsnValLysPheAsnAspValAlaValSerGlyGly                              500505510                                                                     PheTyrGlyProThrAlaAlaGluLeuGlyGlyGlnPheHisHisLys                              515520525                                                                     SerGluAsnGlySerValGlyAlaValPheGlyAlaLysGlnGlnVal                              530535540                                                                     LysLys                                                                        545                                                                           (2) INFORMATION FOR SEQ ID NO:100:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 593 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                                     MetHisPheLysLeuAsnProTyrAlaLeuAlaPheThrSerLeuPhe                              151015                                                                        LeuValAlaCysSerGlyGlyLysGlySerPheAspLeuGluAspVal                              202530                                                                        ArgProAsnGlnThrAlaLysAlaGluLysAlaThrThrSerTyrGln                              354045                                                                        AspGluGluThrLysLysLysThrLysGluGluLeuAspLysLeuMet                              505560                                                                        GluProAlaLeuGlyTyrGluThrGlnIleLeuArgArgAsnLysAla                              65707580                                                                      ProLysThrGluThrGlyGluLysArgAsnGluArgValValGluLeu                              859095                                                                        SerGluAspLysIleThrLysLeuTyrGlnGluSerValGluIleIle                              100105110                                                                     ProHisLeuAspGluLeuAsnGlyLysThrThrSerAsnAspValTyr                              115120125                                                                     HisSerHisAspSerLysArgLeuAspLysAsnArgAspLeuLysTyr                              130135140                                                                     ValArgSerGlyTyrValTyrAspGlySerPheAsnGluIleArgArg                              145150155160                                                                  AsnAspSerGlyPheHisValPheLysGlnGlyIleAspGlyTyrVal                              165170175                                                                     TyrTyrLeuGlyValThrProSerLysGluLeuProLysGlyLysVal                              180185190                                                                     IleSerTyrLysGlyThrTrpAspPheValSerAsnIleAsnLeuGlu                              195200205                                                                     ArgGluIleAspGlyPheAspThrSerGlyAspGlyLysAsnValSer                              210215220                                                                     AlaThrSerIleThrGluThrValAsnArgAspHisLysValGlyGlu                              225230235240                                                                  LysLeuGlyAspAsnGluValLysGlyValAlaHisSerSerGluPhe                              245250255                                                                     AlaValAspPheAspAsnLysLysLeuThrGlySerLeuTyrArgAsn                              260265270                                                                     GlyTyrIleAsnArgAsnLysAlaGlnGluValThrLysArgTyrSer                              275280285                                                                     IleGluAlaAspIleAlaGlyAsnArgPheArgGlyLysAlaLysAla                              290295300                                                                     GluLysAlaGlyAspProIlePheThrAspSerAsnTyrLeuGluGly                              305310315320                                                                  GlyPheTyrGlyProLysAlaGluGluMetAlaGlyLysPhePheThr                              325330335                                                                     AsnAsnLysSerLeuPheAlaValPheAlaAlaLysSerGluAsnGly                              340345350                                                                     GluThrThrThrGluArgIleIleAspAlaThrLysIleAspLeuThr                              355360365                                                                     GlnPheAsnAlaLysGluLeuAsnAsnPheGlyAspAlaSerValLeu                              370375380                                                                     IleIleAspGlyGlnLysIleAspLeuAlaGlyValAsnPheLysAsn                              385390395400                                                                  SerLysThrValGluIleAsnGlyLysThrMetValAlaValAlaCys                              405410415                                                                     CysSerAsnLeuGluTyrMetLysPheGlyGlnLeuTrpGlnLysGlu                              420425430                                                                     GlyLysGlnGlnValLysAspAsnSerLeuPheLeuGlnGlyGluArg                              435440445                                                                     ThrAlaThrAspLysMetProAlaGlyGlyAsnTyrLysTyrValGly                              450455460                                                                     ThrTrpAspAlaLeuValSerLysGlyThrAsnTrpIleAlaGluAla                              465470475480                                                                  AspAsnAsnArgGluSerGlyTyrArgThrGluPheAspValAsnPhe                              485490495                                                                     SerAspLysLysValAsnGlyLysLeuPheAspLysGlyGlyValAsn                              500505510                                                                     ProValPheThrValAspAlaThrIleAsnGlyAsnGlyPheIleGly                              515520525                                                                     SerAlaLysThrSerAspSerGlyPheAlaLeuAspAlaGlySerSer                              530535540                                                                     GlnHisGlyAsnAlaValPheSerAspIleLysValAsnGlyGlyPhe                              545550555560                                                                  TyrGlyProThrAlaGlyGluLeuGlyGlyGlnPheHisHisLysSer                              565570575                                                                     AspAsnGlySerValGlyAlaValPheGlyAlaLysArgGlnIleGlu                              580585590                                                                     Lys                                                                           (2) INFORMATION FOR SEQ ID NO:101:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                                     GluThrGlnSerIleLysAspThrLysGluAlaIleSerSerGluVal                              151015                                                                        AspThr                                                                        (2) INFORMATION FOR SEQ ID NO:102:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 20 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                                     LeuGlnLeuAsnLeuGluLysLysIleGlnGlnAsnTrpLeuThrHis                              151015                                                                        GlnIleAlaPhe                                                                  20                                                                            (2) INFORMATION FOR SEQ ID NO:103:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 23 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                                     MetThrLysLysProTyrPheArgLeuSerIleIleSerCysLeuLeu                              151015                                                                        IleSerCysTyrValLysAla                                                         20                                                                            (2) INFORMATION FOR SEQ ID NO:104:                                            (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                                     MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        Ala                                                                           (2) INFORMATION FOR SEQ ID NO: 105:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5144 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: join(192..695, 2135..4867)                                      (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:                                    CAACATCTGCCCAAGCTATATTCGTTAATGATAAGCCTATTAATGATAAGCCTATTAATG60                ATAAGAAAGAAATTTGTTTTACGCCATTTTTCATATTTTATCCATGAACTTAAAAAATTC120               TAAGTTGACATTATTACAAAAAAAGAACAATAATGCGAATTATTATCAATTTTGTATAAG180               AATATAATTCTATGAAATCTGTACCTCTTATCTCTGGTGGACTTTCCTTT230                         MetLysSerValProLeuIleSerGlyGlyLeuSerPhe                                       1510                                                                          TTATTAAGTGCTTGTAGCGGAGGAGGGTCTTTTGATGTAGATAACGTC278                           LeuLeuSerAlaCysSerGlyGlyGlySerPheAspValAspAsnVal                              152025                                                                        TCTAATCCCTCCTCTTCTAAACCACGTTATCAAGACGATACCTCGAAT326                           SerAsnProSerSerSerLysProArgTyrGlnAspAspThrSerAsn                              30354045                                                                      CAAAGAACAAAATCTGATTTGCAAAAGTTGTCCATTCCTTCTTTAGGG374                           GlnArgThrLysSerAspLeuGlnLysLeuSerIleProSerLeuGly                              505560                                                                        GGAGGGATGAAGTTAGTGGCTCAGAATCTTCTTGGTAAGAAAGAACCT422                           GlyGlyMetLysLeuValAlaGlnAsnLeuLeuGlyLysLysGluPro                              657075                                                                        AGTCTCTTAAATAATGAAGATGGCTATATGATATTTTCCTCACTTTCT470                           SerLeuLeuAsnAsnGluAspGlyTyrMetIlePheSerSerLeuSer                              808590                                                                        ACGATTGAAGAGGATGTTACAAAAGAAAATAAATCTCAGGAACCCACT518                           ThrIleGluGluAspValThrLysGluAsnLysSerGlnGluProThr                              95100105                                                                      ATTGGCTCAATAGACGAGCCTAGCAAAACAAATTCACCCCAAAATCAT566                           IleGlySerIleAspGluProSerLysThrAsnSerProGlnAsnHis                              110115120125                                                                  CATGGCAATATGTATATTCGGGTCTTTATTATATTCAATCGTGGCGTA614                           HisGlyAsnMetTyrIleArgValPheIleIlePheAsnArgGlyVal                              130135140                                                                     ATTCCTCAAATGGCAAGTTTTATTCAGGTTACTATGGATATGCGTATT662                           IleProGlnMetAlaSerPheIleGlnValThrMetAspMetArgIle                              145150155                                                                     ACTTTGGCAAGCAAACAGCCACTACATTACCTGTAGATGGCGAAGCAACGTAT715                      ThrLeuAlaSerLysGlnProLeuHisTyrLeu                                             160165                                                                        AAAGGAACTTGGCACTTCATCACCGCAACTGAAAATGGCAAAAAGTATTCTTTGTTCAGT775               AATGATAGCGGTCAAGCTTATCGCAGACGTAGTGCAATTCCAGAAGATATTGATTTAGAA835               AAAAATGATTCAACTAATGGTGACAAGGGCTTAATAAGTGAATTTAGTGTCAATTTTGGT895               ACAAAAAAGCTCACTGGAAAACTTTATTATAATGAAAGAGAAACAGAACTTAATAAATCA955               AAAGATAGAAAACATACACTCTACAATCTAGAAGCTGAAGTGTATAGTAACCGATTCAGG1015              GGTACAGTAAAGCCAACCGAAAAAGATTCTACAGATCATCCCTTTACCAGCGAGGGAACA1075              TTAGAAGGTGGTTTTTATGGGCCTAAAGGTGAAGAACTAGGAGGAAAGTTTTTAGCTGGC1135              GATAAAAAAGTTTTTGGGGTATTTAGTGCCAAAGAAACGGAAGAAACAAAAAAGAAAGCG1195              TTATCCAAGGAAACCTTAATTGATGGCAAGCTAACTACTTTTAAAACAACCAATGCAACA1255              ACCAATGCAACAGCCAATGCAACAACCAGTACAACAGCCAGTACAACAACCGATGCAGAA1315              AACTTTACGACGAAAGATATACCAAGTTTTGGTGAAGCTGATTACCTTTTAATTGATAAT1375              TACCCTGTTCCTCTTTTACCTGAGAGTGGTGATTTCATAAGTAGTAAGCACCATACTGTA1435              GGAAAGAAAACCTATCAAGTAGAAGCATGTTGCAGTAATCTAAGCTATGTGAAATTTGGT1495              ATGTTTTATGAAGACCCACTTAAAGAAGAAAAAGACAAAGAAAAAGAAGAAGACAAAGAA1555              AAACAAACGGCGGCAACGACCAACACTTATTATCAATTCTTATTAGGTCTCCGTACTGCC1615              AGTTCTGAAATTCCTAAAATGGGAAACGTGGAATATCGCGGTAATTGGTTTGGTTATATT1675              AGTGATGGCACGACATCTTACTCCCCCAGTGGTGATAAGGAACGCAATAAAAATGCTCCC1735              GCCGATTTTAATGTTGATTTTGTCAATAAAAAGCTAACAGGCACATTAAAACGACACGAT1795              AATGGAAATACCGTATTTAGTATTGAGGCAAACTTTAACAGTGGGAATGACTTCACTGGT1855              AAAGCAACCGCAAAAGATTTAGTAATAGATGGTAAAAGTACACAAGCCACATCTAAAGTC1915              AATTTCACGGCAACAGTAAAAGGGGCATTTTATGGACCTGATGCTTCTGAATTAGGCGGT1975              TATTTCACCTATAACGGAAAAAATCCTACAGCTACAAATTCCCCAACCGTATCTTCACCA2035              TCCAATTCAGCAAATGCTCGTGCTGCCGTTGTGTTTGGAGCTAAAAAACAAGTAGACACA2095              ACCAACAAGTAGAAAAAACCAAATAATGGAATACTAAAAATGACTAAAAAACCC2149                    MetThrLysLysPro                                                               170                                                                           TATTTTCGCCTAAGTATTATTTCTTGTCTTTTAATTTCATGCTATGTA2197                          TyrPheArgLeuSerIleIleSerCysLeuLeuIleSerCysTyrVal                              175180185                                                                     AAAGCAGAAACTCAAAGTATAAAAGATACAAAAGAAGCTATATCATCT2245                          LysAlaGluThrGlnSerIleLysAspThrLysGluAlaIleSerSer                              190195200205                                                                  GAAGTGGACACTCAAAGTACAGAAGATTCAGAATTAGAAACTATCTCA2293                          GluValAspThrGlnSerThrGluAspSerGluLeuGluThrIleSer                              210215220                                                                     GTCACTGCAGAAAAAATAAGAGATCGTAAAGATAATGAAGTAACTGGA2341                          ValThrAlaGluLysIleArgAspArgLysAspAsnGluValThrGly                              225230235                                                                     CTTGGCAAAATTATAAAAACGAGTGAAAGTATCAGCCGAGAACAAGTA2389                          LeuGlyLysIleIleLysThrSerGluSerIleSerArgGluGlnVal                              240245250                                                                     TTAAATATTCGTGATCTAACACGCTATGATCCAGGCATTTCAGTTGTA2437                          LeuAsnIleArgAspLeuThrArgTyrAspProGlyIleSerValVal                              255260265                                                                     GAACAAGGTCGCGGTGCAAGTTCTGGATATTCTATTCGTGGTATGGAC2485                          GluGlnGlyArgGlyAlaSerSerGlyTyrSerIleArgGlyMetAsp                              270275280285                                                                  AGAAATAGAGTTGCTTTATTAGTAGATGGTTTACCTCAAACGCAATCT2533                          ArgAsnArgValAlaLeuLeuValAspGlyLeuProGlnThrGlnSer                              290295300                                                                     TATGTAGTGCAAAGCCCTTTAGTTGCTCGTTCAGGATATTCTGGCACT2581                          TyrValValGlnSerProLeuValAlaArgSerGlyTyrSerGlyThr                              305310315                                                                     GGTGCAATTAATGAAATTGAATATGAAAATGTAAAGGCCGTCGAAATA2629                          GlyAlaIleAsnGluIleGluTyrGluAsnValLysAlaValGluIle                              320325330                                                                     AGCAAGGGGGGGAGTTCTTCTGAGTATGGTAATGGAGCACTAGCTGGT2677                          SerLysGlyGlySerSerSerGluTyrGlyAsnGlyAlaLeuAlaGly                              335340345                                                                     TCTGTAACATTTCAAAGCAAATCCGCAGCCGATATCTTAGAAGGAGAC2725                          SerValThrPheGlnSerLysSerAlaAlaAspIleLeuGluGlyAsp                              350355360365                                                                  AAATCATGGGGAATTCAAACTAAAAATGCTTATTCAAGCAAAAATAAA2773                          LysSerTrpGlyIleGlnThrLysAsnAlaTyrSerSerLysAsnLys                              370375380                                                                     GGCTTTACCCATTCTTTAGCTGTAGCAGGAAAACAAGGTGGATTTGAA2821                          GlyPheThrHisSerLeuAlaValAlaGlyLysGlnGlyGlyPheGlu                              385390395                                                                     GGGGTCGCCATTTACACTCAACGAAATTCGGAGGAAACCCAAGTCCAT2869                          GlyValAlaIleTyrThrGlnArgAsnSerGluGluThrGlnValHis                              400405410                                                                     AAAGATGCATTAAAAGGCGTACAAAGTTATGAGCGATTCATCGCCACA2917                          LysAspAlaLeuLysGlyValGlnSerTyrGluArgPheIleAlaThr                              415420425                                                                     ACAGATAAATCTTCAGGATACTTTGTGATACAAGGTGAGTGTCCAAAT2965                          ThrAspLysSerSerGlyTyrPheValIleGlnGlyGluCysProAsn                              430435440445                                                                  GGTGATGACAAGTGTGCAGCCAAACCACCTGCAAAGTTATCCCCCCAA3013                          GlyAspAspLysCysAlaAlaLysProProAlaLysLeuSerProGln                              450455460                                                                     AGCGAAACCGTAAGCGTTTCAGATTATACGGGGGCTAACCGTATCAAA3061                          SerGluThrValSerValSerAspTyrThrGlyAlaAsnArgIleLys                              465470475                                                                     CCTAATCCAATGAAATATGAAAGCCAGTCTTGGTTTTTAAGAGGAGGG3109                          ProAsnProMetLysTyrGluSerGlnSerTrpPheLeuArgGlyGly                              480485490                                                                     TATCATTTTTCTGAACAACACTATATTGGTGGTATTTTTGAATTCACA3157                          TyrHisPheSerGluGlnHisTyrIleGlyGlyIlePheGluPheThr                              495500505                                                                     CAACAAAAATTTGATATCCGTGATATGACATTTCCCGCTTATTTAAGA3205                          GlnGlnLysPheAspIleArgAspMetThrPheProAlaTyrLeuArg                              510515520525                                                                  TCAACAGAAAAACGGGATGATAGAACTGGCCCTTTTTATCCAAAGCAA3253                          SerThrGluLysArgAspAspArgThrGlyProPheTyrProLysGln                              530535540                                                                     GATTATGGTGCATATCAACGTATTGAGGATGGCCGAGGCGTTAACTAT3301                          AspTyrGlyAlaTyrGlnArgIleGluAspGlyArgGlyValAsnTyr                              545550555                                                                     GCAAGTGGGCTTTATTTCGATGAACACCATAGAAAACAGCGTGTAGGT3349                          AlaSerGlyLeuTyrPheAspGluHisHisArgLysGlnArgValGly                              560565570                                                                     ATTGAATATATTTACGAAAATAAGAACAAAGCGGGCATCATTGACAAA3397                          IleGluTyrIleTyrGluAsnLysAsnLysAlaGlyIleIleAspLys                              575580585                                                                     GCAGTGTTAAGTGCTAATCAACAAAACATCATACTTGACAGTTATATG3445                          AlaValLeuSerAlaAsnGlnGlnAsnIleIleLeuAspSerTyrMet                              590595600605                                                                  CGACATACGCATTGCAGTCTTTATCCTAATCCAAGTAAGAATTGCCGC3493                          ArgHisThrHisCysSerLeuTyrProAsnProSerLysAsnCysArg                              610615620                                                                     CCGACACTTGATAAACCTTATTCATACTATCGTTCTGATAGAAATGTT3541                          ProThrLeuAspLysProTyrSerTyrTyrArgSerAspArgAsnVal                              625630635                                                                     TATAAAGAAAAACATAATATGTTGCAATTGAATTTAGAGAAAAAAATT3589                          TyrLysGluLysHisAsnMetLeuGlnLeuAsnLeuGluLysLysIle                              640645650                                                                     CAACAAAATTGGCTTACTCATCAAATTGTCTTCAATCTTGGTTTTGAT3637                          GlnGlnAsnTrpLeuThrHisGlnIleValPheAsnLeuGlyPheAsp                              655660665                                                                     GACTTTACTTCAGCGCTTCAGCATAAAGATTATTTAACTCGACGTGTT3685                          AspPheThrSerAlaLeuGlnHisLysAspTyrLeuThrArgArgVal                              670675680685                                                                  ACCGCTACGGCAAATATTATTTCAGGGACAGTTGCTGGTAAACGAAGA3733                          ThrAlaThrAlaAsnIleIleSerGlyThrValAlaGlyLysArgArg                              690695700                                                                     AATGGTTACGAAAAACAACCTTACTTATACTCAAAACCAAAAGTAGAT3781                          AsnGlyTyrGluLysGlnProTyrLeuTyrSerLysProLysValAsp                              705710715                                                                     TTTGTAGGACAAGATCATTGTAATTATAAAGGTAGCTCCTCTAATTAC3829                          PheValGlyGlnAspHisCysAsnTyrLysGlySerSerSerAsnTyr                              720725730                                                                     AGCGACTGTAAAGTGCGGTTAATTAAAGGGAAAAATTATTATTTCGCA3877                          SerAspCysLysValArgLeuIleLysGlyLysAsnTyrTyrPheAla                              735740745                                                                     GCACGCAATAATATGGCATTAGGGAAATACATTGATTTAGGTTTAGGT3925                          AlaArgAsnAsnMetAlaLeuGlyLysTyrIleAspLeuGlyLeuGly                              750755760765                                                                  ATTCGGTATGACGTATCTCGTACAAAAGCTAATGAATCAACTATTAGT3973                          IleArgTyrAspValSerArgThrLysAlaAsnGluSerThrIleSer                              770775780                                                                     GTTGGTAAATTTAAAAATTTCTCTTGGAATACTGGTATTGTCATAAAA4021                          ValGlyLysPheLysAsnPheSerTrpAsnThrGlyIleValIleLys                              785790795                                                                     CCAACGGAATGGCTTGATCTTTCTTATCGCCTTTCTACTGGATTTAGA4069                          ProThrGluTrpLeuAspLeuSerTyrArgLeuSerThrGlyPheArg                              800805810                                                                     AATCCTAGTTTTGCTGAAATGTATGGTTGGCGGTATGGTGGCAATAAT4117                          AsnProSerPheAlaGluMetTyrGlyTrpArgTyrGlyGlyAsnAsn                              815820825                                                                     AGCGATGTTTATGTAGGTAAATTTAAGCCTGAAACATCTCGTAACCAA4165                          SerAspValTyrValGlyLysPheLysProGluThrSerArgAsnGln                              830835840845                                                                  GAGTTTGGTCTCGCTCTAAAAGGGGATTTTGGTAATATTGAGATCAGT4213                          GluPheGlyLeuAlaLeuLysGlyAspPheGlyAsnIleGluIleSer                              850855860                                                                     CATTTTAGTAATGCTTATCGAAATCTTATCGCCTTTGCTGAAGAACTT4261                          HisPheSerAsnAlaTyrArgAsnLeuIleAlaPheAlaGluGluLeu                              865870875                                                                     AGTAAAAATGGAACTACTGGAAAGGGCAATTATGGATATCATAATGCA4309                          SerLysAsnGlyThrThrGlyLysGlyAsnTyrGlyTyrHisAsnAla                              880885890                                                                     CAAAATGCAAAATTAGTTGGCGTAAATATAACTGCGCAATTAGATTTT4357                          GlnAsnAlaLysLeuValGlyValAsnIleThrAlaGlnLeuAspPhe                              895900905                                                                     AATGGTTTATGGAAACGTATTCCCTACGGTTGGTATGCAACATTTGCT4405                          AsnGlyLeuTrpLysArgIleProTyrGlyTrpTyrAlaThrPheAla                              910915920925                                                                  TATAACCGAGTAAAAGTTAAAGATCAAAAAATCAATGCTGGTTTGGCC4453                          TyrAsnArgValLysValLysAspGlnLysIleAsnAlaGlyLeuAla                              930935940                                                                     TCCGTAAGCAGTTATTTATTTGATGCCATTCAGCCCAGCCGTTATATC4501                          SerValSerSerTyrLeuPheAspAlaIleGlnProSerArgTyrIle                              945950955                                                                     ATTGGTTTAGGCTATGATCATCCAAGTAATACTTGGGGAATTAATACA4549                          IleGlyLeuGlyTyrAspHisProSerAsnThrTrpGlyIleAsnThr                              960965970                                                                     ATGTTTACTCAATCAAAAGCAAAATCTCAAAATGAATTGCTAGGACAA4597                          MetPheThrGlnSerLysAlaLysSerGlnAsnGluLeuLeuGlyGln                              975980985                                                                     CGTGCATTGGGTAACAATTCAAGGAATGTAAAATCAACAAGAAAACTT4645                          ArgAlaLeuGlyAsnAsnSerArgAsnValLysSerThrArgLysLeu                              99099510001005                                                                ACTCGGGCATGGCATATCTTAGATGTATCGGGTTATTACATGGCGAAT4693                          ThrArgAlaTrpHisIleLeuAspValSerGlyTyrTyrMetAlaAsn                              101010151020                                                                  AAAAATATTATGCTTCGATTAGGGATATATAATTTATTCAACTATCGC4741                          LysAsnIleMetLeuArgLeuGlyIleTyrAsnLeuPheAsnTyrArg                              102510301035                                                                  TATGTTACTTGGGAAGCGGTGCGTCAAACAGCACAAGGTGCGGTCAAT4789                          TyrValThrTrpGluAlaValArgGlnThrAlaGlnGlyAlaValAsn                              104010451050                                                                  CAACATCAAAATGTTGGTAGCTATACTCGCTACGCAGCATCAGGACGA4837                          GlnHisGlnAsnValGlySerTyrThrArgTyrAlaAlaSerGlyArg                              105510601065                                                                  AACTATACCTTAACATTAGAAATGAAATTCTAAATTAAAATGCGCCAGAT4887                        AsnTyrThrLeuThrLeuGluMetLysPhe                                                10701075                                                                      GGACTAGATATGCTATATCTATACCTTACTGGCGCATCTTTTTCTGTTCTATAATCTGCT4947              TAAGTGAAAAACCAAACTTGGATTTTTTACAAGATCTTTTCACGCATTTATTGTAAAATC5007              TCCGACAATTTTTACCGCACTTTTCTCTATTACAAAAACAATAAGGATCCTTTTGTGACT5067              CTCTCAATCTTTGGCAAGTTGCTGTTACAACTTCAGATCAAGTTTCAGCCAGCGATCTTA5127              GGCACTTGGGTTCGGCC5144                                                         (2) INFORMATION FOR SEQ ID NO: 106:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 168 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:                                    MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnPro                              202530                                                                        SerSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArgThr                              354045                                                                        LysSerAspLeuGlnLysLeuSerIleProSerLeuGlyGlyGlyMet                              505560                                                                        LysLeuValAlaGlnAsnLeuLeuGlyLysLysGluProSerLeuLeu                              65707580                                                                      AsnAsnGluAspGlyTyrMetIlePheSerSerLeuSerThrIleGlu                              859095                                                                        GluAspValThrLysGluAsnLysSerGlnGluProThrIleGlySer                              100105110                                                                     IleAspGluProSerLysThrAsnSerProGlnAsnHisHisGlyAsn                              115120125                                                                     MetTyrIleArgValPheIleIlePheAsnArgGlyValIleProGln                              130135140                                                                     MetAlaSerPheIleGlnValThrMetAspMetArgIleThrLeuAla                              145150155160                                                                  SerLysGlnProLeuHisTyrLeu                                                      165                                                                           (2) INFORMATION FOR SEQ ID NO: 107:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 911 amino acids                                                   (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107:                                    MetThrLysLysProTyrPheArgLeuSerIleIleSerCysLeuLeu                              151015                                                                        IleSerCysTyrValLysAlaGluThrGlnSerIleLysAspThrLys                              202530                                                                        GluAlaIleSerSerGluValAspThrGlnSerThrGluAspSerGlu                              354045                                                                        LeuGluThrIleSerValThrAlaGluLysIleArgAspArgLysAsp                              505560                                                                        AsnGluValThrGlyLeuGlyLysIleIleLysThrSerGluSerIle                              65707580                                                                      SerArgGluGlnValLeuAsnIleArgAspLeuThrArgTyrAspPro                              859095                                                                        GlyIleSerValValGluGlnGlyArgGlyAlaSerSerGlyTyrSer                              100105110                                                                     IleArgGlyMetAspArgAsnArgValAlaLeuLeuValAspGlyLeu                              115120125                                                                     ProGlnThrGlnSerTyrValValGlnSerProLeuValAlaArgSer                              130135140                                                                     GlyTyrSerGlyThrGlyAlaIleAsnGluIleGluTyrGluAsnVal                              145150155160                                                                  LysAlaValGluIleSerLysGlyGlySerSerSerGluTyrGlyAsn                              165170175                                                                     GlyAlaLeuAlaGlySerValThrPheGlnSerLysSerAlaAlaAsp                              180185190                                                                     IleLeuGluGlyAspLysSerTrpGlyIleGlnThrLysAsnAlaTyr                              195200205                                                                     SerSerLysAsnLysGlyPheThrHisSerLeuAlaValAlaGlyLys                              210215220                                                                     GlnGlyGlyPheGluGlyValAlaIleTyrThrGlnArgAsnSerGlu                              225230235240                                                                  GluThrGlnValHisLysAspAlaLeuLysGlyValGlnSerTyrGlu                              245250255                                                                     ArgPheIleAlaThrThrAspLysSerSerGlyTyrPheValIleGln                              260265270                                                                     GlyGluCysProAsnGlyAspAspLysCysAlaAlaLysProProAla                              275280285                                                                     LysLeuSerProGlnSerGluThrValSerValSerAspTyrThrGly                              290295300                                                                     AlaAsnArgIleLysProAsnProMetLysTyrGluSerGlnSerTrp                              305310315320                                                                  PheLeuArgGlyGlyTyrHisPheSerGluGlnHisTyrIleGlyGly                              325330335                                                                     IlePheGluPheThrGlnGlnLysPheAspIleArgAspMetThrPhe                              340345350                                                                     ProAlaTyrLeuArgSerThrGluLysArgAspAspArgThrGlyPro                              355360365                                                                     PheTyrProLysGlnAspTyrGlyAlaTyrGlnArgIleGluAspGly                              370375380                                                                     ArgGlyValAsnTyrAlaSerGlyLeuTyrPheAspGluHisHisArg                              385390395400                                                                  LysGlnArgValGlyIleGluTyrIleTyrGluAsnLysAsnLysAla                              405410415                                                                     GlyIleIleAspLysAlaValLeuSerAlaAsnGlnGlnAsnIleIle                              420425430                                                                     LeuAspSerTyrMetArgHisThrHisCysSerLeuTyrProAsnPro                              435440445                                                                     SerLysAsnCysArgProThrLeuAspLysProTyrSerTyrTyrArg                              450455460                                                                     SerAspArgAsnValTyrLysGluLysHisAsnMetLeuGlnLeuAsn                              465470475480                                                                  LeuGluLysLysIleGlnGlnAsnTrpLeuThrHisGlnIleValPhe                              485490495                                                                     AsnLeuGlyPheAspAspPheThrSerAlaLeuGlnHisLysAspTyr                              500505510                                                                     LeuThrArgArgValThrAlaThrAlaAsnIleIleSerGlyThrVal                              515520525                                                                     AlaGlyLysArgArgAsnGlyTyrGluLysGlnProTyrLeuTyrSer                              530535540                                                                     LysProLysValAspPheValGlyGlnAspHisCysAsnTyrLysGly                              545550555560                                                                  SerSerSerAsnTyrSerAspCysLysValArgLeuIleLysGlyLys                              565570575                                                                     AsnTyrTyrPheAlaAlaArgAsnAsnMetAlaLeuGlyLysTyrIle                              580585590                                                                     AspLeuGlyLeuGlyIleArgTyrAspValSerArgThrLysAlaAsn                              595600605                                                                     GluSerThrIleSerValGlyLysPheLysAsnPheSerTrpAsnThr                              610615620                                                                     GlyIleValIleLysProThrGluTrpLeuAspLeuSerTyrArgLeu                              625630635640                                                                  SerThrGlyPheArgAsnProSerPheAlaGluMetTyrGlyTrpArg                              645650655                                                                     TyrGlyGlyAsnAsnSerAspValTyrValGlyLysPheLysProGlu                              660665670                                                                     ThrSerArgAsnGlnGluPheGlyLeuAlaLeuLysGlyAspPheGly                              675680685                                                                     AsnIleGluIleSerHisPheSerAsnAlaTyrArgAsnLeuIleAla                              690695700                                                                     PheAlaGluGluLeuSerLysAsnGlyThrThrGlyLysGlyAsnTyr                              705710715720                                                                  GlyTyrHisAsnAlaGlnAsnAlaLysLeuValGlyValAsnIleThr                              725730735                                                                     AlaGlnLeuAspPheAsnGlyLeuTrpLysArgIleProTyrGlyTrp                              740745750                                                                     TyrAlaThrPheAlaTyrAsnArgValLysValLysAspGlnLysIle                              755760765                                                                     AsnAlaGlyLeuAlaSerValSerSerTyrLeuPheAspAlaIleGln                              770775780                                                                     ProSerArgTyrIleIleGlyLeuGlyTyrAspHisProSerAsnThr                              785790795800                                                                  TrpGlyIleAsnThrMetPheThrGlnSerLysAlaLysSerGlnAsn                              805810815                                                                     GluLeuLeuGlyGlnArgAlaLeuGlyAsnAsnSerArgAsnValLys                              820825830                                                                     SerThrArgLysLeuThrArgAlaTrpHisIleLeuAspValSerGly                              835840845                                                                     TyrTyrMetAlaAsnLysAsnIleMetLeuArgLeuGlyIleTyrAsn                              850855860                                                                     LeuPheAsnTyrArgTyrValThrTrpGluAlaValArgGlnThrAla                              865870875880                                                                  GlnGlyAlaValAsnGlnHisGlnAsnValGlySerTyrThrArgTyr                              885890895                                                                     AlaAlaSerGlyArgAsnTyrThrLeuThrLeuGluMetLysPhe                                 900905910                                                                     (2) INFORMATION FOR SEQ ID NO: 108:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1993 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 3..1946                                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108:                                    ATATGAAATCTGTACCTCTTATCTCTGGTGGACTTTCCTTTTTATTA47                             MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeu                                 151015                                                                        AGTGCTTGTAGCGGGGGAGGTGGTTCTTTTGATGTAGATGACGTCTCT95                            SerAlaCysSerGlyGlyGlyGlySerPheAspValAspAspValSer                              202530                                                                        AATCCCTCCTCTTCTAAACCACGTTATCAAGACGATACTTCAAGTTCA143                           AsnProSerSerSerLysProArgTyrGlnAspAspThrSerSerSer                              354045                                                                        AGAACAAAATCTAAATTGGAAAATTTGTCCATTCCTTCTTTAGGGGGA191                           ArgThrLysSerLysLeuGluAsnLeuSerIleProSerLeuGlyGly                              505560                                                                        GGGATGAAGTTAGTGGCTCAGAATCTTCGTGATAGGACAAAACCTAGT239                           GlyMetLysLeuValAlaGlnAsnLeuArgAspArgThrLysProSer                              657075                                                                        CTCTTAAATGAAGATGACTATATGATATTTTCCTCACTTTCAACGATT287                           LeuLeuAsnGluAspAspTyrMetIlePheSerSerLeuSerThrIle                              80859095                                                                      AAAGCTGATGTTGAAAAAGAAAATAAACACTATACAAGTCCAGTTGGC335                           LysAlaAspValGluLysGluAsnLysHisTyrThrSerProValGly                              100105110                                                                     TCAATAGACGAGCCTAGTACAACAAATCCAAAAGAAAATGATCATGGA383                           SerIleAspGluProSerThrThrAsnProLysGluAsnAspHisGly                              115120125                                                                     CAAAGATATGTATATTCAGGACTTTATTATATTCCATCGTGGAATTTA431                           GlnArgTyrValTyrSerGlyLeuTyrTyrIleProSerTrpAsnLeu                              130135140                                                                     AACGATCTTAAAAATAACAAGTATTATTATTCTGGTTACTATGGATAT479                           AsnAspLeuLysAsnAsnLysTyrTyrTyrSerGlyTyrTyrGlyTyr                              145150155                                                                     GCGTATTACTTTGGCAAGCAAACAGCCACTACATTACCTGTAAATGGC527                           AlaTyrTyrPheGlyLysGlnThrAlaThrThrLeuProValAsnGly                              160165170175                                                                  AAAGTAACGTATAAAGGAACTTGGAGCTTCATCACCGCAGCTGAAAAT575                           LysValThrTyrLysGlyThrTrpSerPheIleThrAlaAlaGluAsn                              180185190                                                                     GGCAAAAGGTATCCTTTGTTAAGTAATGGCAGTCAAGCTTATTTTCGA623                           GlyLysArgTyrProLeuLeuSerAsnGlySerGlnAlaTyrPheArg                              195200205                                                                     CGTAGTGCAATTCCAGAAGATATTGATTTAGAAGTTAAAAATGATGAG671                           ArgSerAlaIleProGluAspIleAspLeuGluValLysAsnAspGlu                              210215220                                                                     AATAGAGAAAAAGGGCTAGTGAGTGAATTTAGTGCAGATTTTGGGACT719                           AsnArgGluLysGlyLeuValSerGluPheSerAlaAspPheGlyThr                              225230235                                                                     AAAAAACTGACAGGAGGACTGTTTTACACCAAAAGACAAACTCATATT767                           LysLysLeuThrGlyGlyLeuPheTyrThrLysArgGlnThrHisIle                              240245250255                                                                  CAAAACCATGAAAAGAAAAAACTCTATGATATAGATGCCCATATTTAT815                           GlnAsnHisGluLysLysLysLeuTyrAspIleAspAlaHisIleTyr                              260265270                                                                     AGTAATAGATTCAGAGGTAAAGTAAATCCTACCCAAAAAGATTCTAAA863                           SerAsnArgPheArgGlyLysValAsnProThrGlnLysAspSerLys                              275280285                                                                     GAACATCCCTTTACCAGCGAGGGAACATTAGAAGGTGGTTTTTACGGG911                           GluHisProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGly                              290295300                                                                     CCTGAAGGTCAAGAATTAGGAGGAAAGTTTTTAGCTGGCGACAAAAAA959                           ProGluGlyGlnGluLeuGlyGlyLysPheLeuAlaGlyAspLysLys                              305310315                                                                     GTTTTTGGGGTATTTAGTGCCAAAGGAACGGAAGAAAACAAAAAATTA1007                          ValPheGlyValPheSerAlaLysGlyThrGluGluAsnLysLysLeu                              320325330335                                                                  CCCAAAGAAACCTTAATTGATGGCAAGCTAACTACTTTCTCTACTAAA1055                          ProLysGluThrLeuIleAspGlyLysLeuThrThrPheSerThrLys                              340345350                                                                     ACAACCGATGCAAAAACCAATGCAACAGCCAATGCAACAACCAGTACC1103                          ThrThrAspAlaLysThrAsnAlaThrAlaAsnAlaThrThrSerThr                              355360365                                                                     GCAGCCAATACAACAACCGATACAACAGCCAATACAATAACCGATGCA1151                          AlaAlaAsnThrThrThrAspThrThrAlaAsnThrIleThrAspAla                              370375380                                                                     GAAAACTTTAAGACGAAAGATATATCAAGTTTTGGTGAAGCTGATTAC1199                          GluAsnPheLysThrLysAspIleSerSerPheGlyGluAlaAspTyr                              385390395                                                                     CTTTTAATTGATAATTACCCTGTTCCTCTTTTACCTGAGAGTGGTGAT1247                          LeuLeuIleAspAsnTyrProValProLeuLeuProGluSerGlyAsp                              400405410415                                                                  TTCATAAGTAGTAAGCACCATACTGTAGGAAAGAAAACCTATCAAGTA1295                          PheIleSerSerLysHisHisThrValGlyLysLysThrTyrGlnVal                              420425430                                                                     AAAGCATGTTGCAGTAATCTAAGCTATGTGAAATTTGGTATGTATTAT1343                          LysAlaCysCysSerAsnLeuSerTyrValLysPheGlyMetTyrTyr                              435440445                                                                     GAAGTCCCACCTAAAGAAGAAGAAAAAGACAAAGAAAAAAAAGAAAAA1391                          GluValProProLysGluGluGluLysAspLysGluLysLysGluLys                              450455460                                                                     GAAAAAGAAAAACAAGCGACAAATCTATCGAACACTTATTATCAATTC1439                          GluLysGluLysGlnAlaThrAsnLeuSerAsnThrTyrTyrGlnPhe                              465470475                                                                     TTATTAGGTCTCCGTACTCCCAGTTCTGAAATTCCTAAAGGAGGAAGT1487                          LeuLeuGlyLeuArgThrProSerSerGluIleProLysGlyGlySer                              480485490495                                                                  GCAAAATATCTCGGTAGTTGGTTTGGTTATCTGAGCGATGGTTCAACA1535                          AlaLysTyrLeuGlySerTrpPheGlyTyrLeuSerAspGlySerThr                              500505510                                                                     TCTTACTCCCCCAGTGGTGATAAGAAACGCGAGAACAATGCTCTCGCC1583                          SerTyrSerProSerGlyAspLysLysArgGluAsnAsnAlaLeuAla                              515520525                                                                     GAGTTTAATGTAAATTTTGTCGATAAAACATTAAAAGGCCAATTAATA1631                          GluPheAsnValAsnPheValAspLysThrLeuLysGlyGlnLeuIle                              530535540                                                                     CGACACGATAATCAAAATACCGTTTTTACAATTGATGCAACCTTTAAA1679                          ArgHisAspAsnGlnAsnThrValPheThrIleAspAlaThrPheLys                              545550555                                                                     GGTGGTAAGAATAACTTCACTGGTACAGCAACCGCAAACAATGTAGCG1727                          GlyGlyLysAsnAsnPheThrGlyThrAlaThrAlaAsnAsnValAla                              560565570575                                                                  ATTGATCCCCAAAGTACACAAGGCACATCTAACGTCAATTTCACGGCA1775                          IleAspProGlnSerThrGlnGlyThrSerAsnValAsnPheThrAla                              580585590                                                                     ACAGTAAATGGGGCATTTTATGGGCCGAACGCTACAGAATTAGGCGGT1823                          ThrValAsnGlyAlaPheTyrGlyProAsnAlaThrGluLeuGlyGly                              595600605                                                                     TATTTCACCTATAACGGAAATCCTACAGATAAAAGTTCCTCAACCGTA1871                          TyrPheThrTyrAsnGlyAsnProThrAspLysSerSerSerThrVal                              610615620                                                                     CCTTCATCATCCAATTCAAAAAATGCAAGAGCTGCAGTTGTCTTTGGT1919                          ProSerSerSerAsnSerLysAsnAlaArgAlaAlaValValPheGly                              625630635                                                                     GCGAGACAACAAGTAGAAACAACCAAATAATGGAATACTAAAAATGA1966                           AlaArgGlnGlnValGluThrThrLys                                                   640645                                                                        CTAAAAAAGCTTCTAGAAGCCGAATTC1993                                               (2) INFORMATION FOR SEQ ID NO: 109:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 648 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109:                                    MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlyGlySerPheAspValAspAspValSerAsn                              202530                                                                        ProSerSerSerLysProArgTyrGlnAspAspThrSerSerSerArg                              354045                                                                        ThrLysSerLysLeuGluAsnLeuSerIleProSerLeuGlyGlyGly                              505560                                                                        MetLysLeuValAlaGlnAsnLeuArgAspArgThrLysProSerLeu                              65707580                                                                      LeuAsnGluAspAspTyrMetIlePheSerSerLeuSerThrIleLys                              859095                                                                        AlaAspValGluLysGluAsnLysHisTyrThrSerProValGlySer                              100105110                                                                     IleAspGluProSerThrThrAsnProLysGluAsnAspHisGlyGln                              115120125                                                                     ArgTyrValTyrSerGlyLeuTyrTyrIleProSerTrpAsnLeuAsn                              130135140                                                                     AspLeuLysAsnAsnLysTyrTyrTyrSerGlyTyrTyrGlyTyrAla                              145150155160                                                                  TyrTyrPheGlyLysGlnThrAlaThrThrLeuProValAsnGlyLys                              165170175                                                                     ValThrTyrLysGlyThrTrpSerPheIleThrAlaAlaGluAsnGly                              180185190                                                                     LysArgTyrProLeuLeuSerAsnGlySerGlnAlaTyrPheArgArg                              195200205                                                                     SerAlaIleProGluAspIleAspLeuGluValLysAsnAspGluAsn                              210215220                                                                     ArgGluLysGlyLeuValSerGluPheSerAlaAspPheGlyThrLys                              225230235240                                                                  LysLeuThrGlyGlyLeuPheTyrThrLysArgGlnThrHisIleGln                              245250255                                                                     AsnHisGluLysLysLysLeuTyrAspIleAspAlaHisIleTyrSer                              260265270                                                                     AsnArgPheArgGlyLysValAsnProThrGlnLysAspSerLysGlu                              275280285                                                                     HisProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyPro                              290295300                                                                     GluGlyGlnGluLeuGlyGlyLysPheLeuAlaGlyAspLysLysVal                              305310315320                                                                  PheGlyValPheSerAlaLysGlyThrGluGluAsnLysLysLeuPro                              325330335                                                                     LysGluThrLeuIleAspGlyLysLeuThrThrPheSerThrLysThr                              340345350                                                                     ThrAspAlaLysThrAsnAlaThrAlaAsnAlaThrThrSerThrAla                              355360365                                                                     AlaAsnThrThrThrAspThrThrAlaAsnThrIleThrAspAlaGlu                              370375380                                                                     AsnPheLysThrLysAspIleSerSerPheGlyGluAlaAspTyrLeu                              385390395400                                                                  LeuIleAspAsnTyrProValProLeuLeuProGluSerGlyAspPhe                              405410415                                                                     IleSerSerLysHisHisThrValGlyLysLysThrTyrGlnValLys                              420425430                                                                     AlaCysCysSerAsnLeuSerTyrValLysPheGlyMetTyrTyrGlu                              435440445                                                                     ValProProLysGluGluGluLysAspLysGluLysLysGluLysGlu                              450455460                                                                     LysGluLysGlnAlaThrAsnLeuSerAsnThrTyrTyrGlnPheLeu                              465470475480                                                                  LeuGlyLeuArgThrProSerSerGluIleProLysGlyGlySerAla                              485490495                                                                     LysTyrLeuGlySerTrpPheGlyTyrLeuSerAspGlySerThrSer                              500505510                                                                     TyrSerProSerGlyAspLysLysArgGluAsnAsnAlaLeuAlaGlu                              515520525                                                                     PheAsnValAsnPheValAspLysThrLeuLysGlyGlnLeuIleArg                              530535540                                                                     HisAspAsnGlnAsnThrValPheThrIleAspAlaThrPheLysGly                              545550555560                                                                  GlyLysAsnAsnPheThrGlyThrAlaThrAlaAsnAsnValAlaIle                              565570575                                                                     AspProGlnSerThrGlnGlyThrSerAsnValAsnPheThrAlaThr                              580585590                                                                     ValAsnGlyAlaPheTyrGlyProAsnAlaThrGluLeuGlyGlyTyr                              595600605                                                                     PheThrTyrAsnGlyAsnProThrAspLysSerSerSerThrValPro                              610615620                                                                     SerSerSerAsnSerLysAsnAlaArgAlaAlaValValPheGlyAla                              625630635640                                                                  ArgGlnGlnValGluThrThrLys                                                      645                                                                           (2) INFORMATION FOR SEQ ID NO: 110:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1974 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 20..1912                                                        (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110:                                    GAATTCGGCTTGGATCCATATGAAATCTGTACCTCTTATCTCTGGTGGACTT52                        MetLysSerValProLeuIleSerGlyGlyLeu                                             1510                                                                          TCCTTTTTACTAAGTGCTTGTAGCGGAGGGGGGTCTTTTGATGTAGAT100                           SerPheLeuLeuSerAlaCysSerGlyGlyGlySerPheAspValAsp                              152025                                                                        AACGTCTCTAATCCATCCTCTTCTAAACCACGTTATCAAGACGATACT148                           AsnValSerAsnProSerSerSerLysProArgTyrGlnAspAspThr                              303540                                                                        TCAAGTTCAAGAACAAAATCTAATTTGAAAAAGTTGTCCATTCCTTCT196                           SerSerSerArgThrLysSerAsnLeuLysLysLeuSerIleProSer                              455055                                                                        TTAGGGGGAGGGATGAAGTTAGTGGCTCAGAATCTTAGTGATAAGAAC244                           LeuGlyGlyGlyMetLysLeuValAlaGlnAsnLeuSerAspLysAsn                              60657075                                                                      AAACCTAGTCTCTTAAATGAAGATGACTATATATCATATTTTTCCTCA292                           LysProSerLeuLeuAsnGluAspAspTyrIleSerTyrPheSerSer                              808590                                                                        CTTTCTACAATTCAAGATGATGTTAAAAAAGAAAATAAACGCCATACA340                           LeuSerThrIleGlnAspAspValLysLysGluAsnLysArgHisThr                              95100105                                                                      AATCCAGTTGGCTCAATAGACGAGCCTAACGCAACAAATCCACCCGAA388                           AsnProValGlySerIleAspGluProAsnAlaThrAsnProProGlu                              110115120                                                                     AAGCATCATGGACAAAGATATGTATATTCAGGGCTTTATTATATTCCA436                           LysHisHisGlyGlnArgTyrValTyrSerGlyLeuTyrTyrIlePro                              125130135                                                                     TCGTGGAGTCATTCCTCAAATGGCAAGCTTTATTTAGGTTACTATGGA484                           SerTrpSerHisSerSerAsnGlyLysLeuTyrLeuGlyTyrTyrGly                              140145150155                                                                  TATGCGTTTTATTATGGTAATAAAACTGCAACAAACTTGCCAGTAAGC532                           TyrAlaPheTyrTyrGlyAsnLysThrAlaThrAsnLeuProValSer                              160165170                                                                     GGCATAGCTAAATACAAAGGAACTTGGGATTTTATTACTGCAACTAAA580                           GlyIleAlaLysTyrLysGlyThrTrpAspPheIleThrAlaThrLys                              175180185                                                                     AATGGCCAACGTTATTCTTTATTTGGTAGCGCTTTTGGAGCTTATAAT628                           AsnGlyGlnArgTyrSerLeuPheGlySerAlaPheGlyAlaTyrAsn                              190195200                                                                     AGACGCAGTGCTATTTCAGAAGATATAGATAATTTAGAAAATAATCTA676                           ArgArgSerAlaIleSerGluAspIleAspAsnLeuGluAsnAsnLeu                              205210215                                                                     AAGAATGGTGCGGGATTAACTAGTGAATTTACTGTCAATTTTGGTACG724                           LysAsnGlyAlaGlyLeuThrSerGluPheThrValAsnPheGlyThr                              220225230235                                                                  AAAAAGCTCACTGGAAAACTTTATTATAATGAAAGGGAAACAAATCTT772                           LysLysLeuThrGlyLysLeuTyrTyrAsnGluArgGluThrAsnLeu                              240245250                                                                     AATAAATTACAAAAGAGAAAACATGAACTCTATGATATAGATGCCGAT820                           AsnLysLeuGlnLysArgLysHisGluLeuTyrAspIleAspAlaAsp                              255260265                                                                     ATTTATAGTAATAGATTCAGAGGTAAAGTAAAGCCAACAACCCAAAAA868                           IleTyrSerAsnArgPheArgGlyLysValLysProThrThrGlnLys                              270275280                                                                     GATTCTCAAGAACATCCCTTTACCAGCGAGGGAACATTAGAAGGTGGT916                           AspSerGlnGluHisProPheThrSerGluGlyThrLeuGluGlyGly                              285290295                                                                     TTTTATGGGCCTAACGGTGAAGAATTAGGAGGAAAGTTTTTAGCTGGC964                           PheTyrGlyProAsnGlyGluGluLeuGlyGlyLysPheLeuAlaGly                              300305310315                                                                  GATAACCGAGTTTTTGGGGTATTTAGTGCCAAAGAAGAAGAAACAAAA1012                          AspAsnArgValPheGlyValPheSerAlaLysGluGluGluThrLys                              320325330                                                                     GACAAAAAATTATCCAGAGAAACCTTAATTGATGGCAAGCTAATTACT1060                          AspLysLysLeuSerArgGluThrLeuIleAspGlyLysLeuIleThr                              335340345                                                                     TTTAAAAGAACTGATGCAACAACCAATACAGCAGCCAATGCAAAAACC1108                          PheLysArgThrAspAlaThrThrAsnThrAlaAlaAsnAlaLysThr                              350355360                                                                     GATGAAAAAAACTTTACGACGAAAGATATACCAAGTTTTGGTGAAGCT1156                          AspGluLysAsnPheThrThrLysAspIleProSerPheGlyGluAla                              365370375                                                                     GATTACCTTTTAATTGATAATTACCCTGTTCCTCTTTTCCCTGAAGAA1204                          AspTyrLeuLeuIleAspAsnTyrProValProLeuPheProGluGlu                              380385390395                                                                  AATACTAATGATTTCATAACTAGTAGGCACCATAAGGTAGGAGATAAA1252                          AsnThrAsnAspPheIleThrSerArgHisHisLysValGlyAspLys                              400405410                                                                     ACCTATAAAGTAGAAGCATGTTGCAAGAATCTAAGCTATGTGAAATTT1300                          ThrTyrLysValGluAlaCysCysLysAsnLeuSerTyrValLysPhe                              415420425                                                                     GGTATGTATTATGAAGACCCATTAAATGGAGAAAATGGCAAAGAAAAA1348                          GlyMetTyrTyrGluAspProLeuAsnGlyGluAsnGlyLysGluLys                              430435440                                                                     GAAAAAGAAAAAGAAAAAGACAAAGAAAAACAAGCGACAACATCTATC1396                          GluLysGluLysGluLysAspLysGluLysGlnAlaThrThrSerIle                              445450455                                                                     AAGACTTATTATCAATTCTTATTAGGTCACCGTACTGCCAAGGCCGAC1444                          LysThrTyrTyrGlnPheLeuLeuGlyHisArgThrAlaLysAlaAsp                              460465470475                                                                  ATACCTGCAACGGGAAACGTGAAATATCGCGGTAATTGGTTTGGTTAT1492                          IleProAlaThrGlyAsnValLysTyrArgGlyAsnTrpPheGlyTyr                              480485490                                                                     ATTGGTGATGACAAGACATCTTACTCCACTACTGGAGATAAAAATGCT1540                          IleGlyAspAspLysThrSerTyrSerThrThrGlyAspLysAsnAla                              495500505                                                                     GTCGCCGAGTTTGATGTAAATTTTGCCGATAAAACATTAACAGGCACA1588                          ValAlaGluPheAspValAsnPheAlaAspLysThrLeuThrGlyThr                              510515520                                                                     TTAAAACGACACGATAATGGAAATCCCGTATTTACAATTAATGCAAGC1636                          LeuLysArgHisAspAsnGlyAsnProValPheThrIleAsnAlaSer                              525530535                                                                     TTTCAAAGTGGTAAGAATGACTTCACTGGTACAGCAACCGCAAACAAT1684                          PheGlnSerGlyLysAsnAspPheThrGlyThrAlaThrAlaAsnAsn                              540545550555                                                                  GTAGCGATTGATCCCCAAAATACACAAACCACATCTAGAGTCAATTTC1732                          ValAlaIleAspProGlnAsnThrGlnThrThrSerArgValAsnPhe                              560565570                                                                     ACGGCAACAGTAAACGGGGCATTTTATGGACCTAAGGCTACAGAATTA1780                          ThrAlaThrValAsnGlyAlaPheTyrGlyProLysAlaThrGluLeu                              575580585                                                                     GGCGGTTATTTCACTTATAACGGAAACAATCCTACAGATAAAAATTCC1828                          GlyGlyTyrPheThrTyrAsnGlyAsnAsnProThrAspLysAsnSer                              590595600                                                                     TCAACCGTTTCACCATCCAATTCAGCAAATGCTCGTGCTGCCGTTGTG1876                          SerThrValSerProSerAsnSerAlaAsnAlaArgAlaAlaValVal                              605610615                                                                     TTTGGCGCTAAAAAACAAGTAGAAACAACCAACAAGTAAAAACAAC1922                            PheGlyAlaLysLysGlnValGluThrThrAsnLys                                          620625630                                                                     CAAGTAATGGAATACTAAAAATGACTAAAAAAGCTTCTAGAAAGCCGAATTC1974                      (2) INFORMATION FOR SEQ ID NO: 111:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 631 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111:                                    MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnPro                              202530                                                                        SerSerSerLysProArgTyrGlnAspAspThrSerSerSerArgThr                              354045                                                                        LysSerAsnLeuLysLysLeuSerIleProSerLeuGlyGlyGlyMet                              505560                                                                        LysLeuValAlaGlnAsnLeuSerAspLysAsnLysProSerLeuLeu                              65707580                                                                      AsnGluAspAspTyrIleSerTyrPheSerSerLeuSerThrIleGln                              859095                                                                        AspAspValLysLysGluAsnLysArgHisThrAsnProValGlySer                              100105110                                                                     IleAspGluProAsnAlaThrAsnProProGluLysHisHisGlyGln                              115120125                                                                     ArgTyrValTyrSerGlyLeuTyrTyrIleProSerTrpSerHisSer                              130135140                                                                     SerAsnGlyLysLeuTyrLeuGlyTyrTyrGlyTyrAlaPheTyrTyr                              145150155160                                                                  GlyAsnLysThrAlaThrAsnLeuProValSerGlyIleAlaLysTyr                              165170175                                                                     LysGlyThrTrpAspPheIleThrAlaThrLysAsnGlyGlnArgTyr                              180185190                                                                     SerLeuPheGlySerAlaPheGlyAlaTyrAsnArgArgSerAlaIle                              195200205                                                                     SerGluAspIleAspAsnLeuGluAsnAsnLeuLysAsnGlyAlaGly                              210215220                                                                     LeuThrSerGluPheThrValAsnPheGlyThrLysLysLeuThrGly                              225230235240                                                                  LysLeuTyrTyrAsnGluArgGluThrAsnLeuAsnLysLeuGlnLys                              245250255                                                                     ArgLysHisGluLeuTyrAspIleAspAlaAspIleTyrSerAsnArg                              260265270                                                                     PheArgGlyLysValLysProThrThrGlnLysAspSerGlnGluHis                              275280285                                                                     ProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsn                              290295300                                                                     GlyGluGluLeuGlyGlyLysPheLeuAlaGlyAspAsnArgValPhe                              305310315320                                                                  GlyValPheSerAlaLysGluGluGluThrLysAspLysLysLeuSer                              325330335                                                                     ArgGluThrLeuIleAspGlyLysLeuIleThrPheLysArgThrAsp                              340345350                                                                     AlaThrThrAsnThrAlaAlaAsnAlaLysThrAspGluLysAsnPhe                              355360365                                                                     ThrThrLysAspIleProSerPheGlyGluAlaAspTyrLeuLeuIle                              370375380                                                                     AspAsnTyrProValProLeuPheProGluGluAsnThrAsnAspPhe                              385390395400                                                                  IleThrSerArgHisHisLysValGlyAspLysThrTyrLysValGlu                              405410415                                                                     AlaCysCysLysAsnLeuSerTyrValLysPheGlyMetTyrTyrGlu                              420425430                                                                     AspProLeuAsnGlyGluAsnGlyLysGluLysGluLysGluLysGlu                              435440445                                                                     LysAspLysGluLysGlnAlaThrThrSerIleLysThrTyrTyrGln                              450455460                                                                     PheLeuLeuGlyHisArgThrAlaLysAlaAspIleProAlaThrGly                              465470475480                                                                  AsnValLysTyrArgGlyAsnTrpPheGlyTyrIleGlyAspAspLys                              485490495                                                                     ThrSerTyrSerThrThrGlyAspLysAsnAlaValAlaGluPheAsp                              500505510                                                                     ValAsnPheAlaAspLysThrLeuThrGlyThrLeuLysArgHisAsp                              515520525                                                                     AsnGlyAsnProValPheThrIleAsnAlaSerPheGlnSerGlyLys                              530535540                                                                     AsnAspPheThrGlyThrAlaThrAlaAsnAsnValAlaIleAspPro                              545550555560                                                                  GlnAsnThrGlnThrThrSerArgValAsnPheThrAlaThrValAsn                              565570575                                                                     GlyAlaPheTyrGlyProLysAlaThrGluLeuGlyGlyTyrPheThr                              580585590                                                                     TyrAsnGlyAsnAsnProThrAspLysAsnSerSerThrValSerPro                              595600605                                                                     SerAsnSerAlaAsnAlaArgAlaAlaValValPheGlyAlaLysLys                              610615620                                                                     GlnValGluThrThrAsnLys                                                         625630                                                                        (2) INFORMATION FOR SEQ ID NO: 112:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1951 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..1890                                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112:                                    ATGAAATCTGTACCTCTTATCTCTGGTGGACTTTCCCTTTTATTAAGT48                            MetLysSerValProLeuIleSerGlyGlyLeuSerLeuLeuLeuSer                              151015                                                                        GCTTGTAGCGGGGGAGGTGGTTCTTTTGATGTAGATGACGTCTCTAAT96                            AlaCysSerGlyGlyGlyGlySerPheAspValAspAspValSerAsn                              202530                                                                        CCCTCCTCTTCTAAACCACGTTATCAAGACGATACCTCGAGTCAAAGA144                           ProSerSerSerLysProArgTyrGlnAspAspThrSerSerGlnArg                              354045                                                                        ACAAAATCTAATTTGGAAAAGTTGTCCATTCCTTCTTTAGGAGGAGGG192                           ThrLysSerAsnLeuGluLysLeuSerIleProSerLeuGlyGlyGly                              505560                                                                        ATGAAATTGGTGGCTCAGAATCTGAGTGGTAATAAAGAACCTAGTTTC240                           MetLysLeuValAlaGlnAsnLeuSerGlyAsnLysGluProSerPhe                              65707580                                                                      TTAAATGGAAATGACTATATGATATTTTCCTCACGTTCTACGATTAAA288                           LeuAsnGlyAsnAspTyrMetIlePheSerSerArgSerThrIleLys                              859095                                                                        GATGATGTTGAAAATAACAATACAAACGGGGGGGACTATATTGGCTCA336                           AspAspValGluAsnAsnAsnThrAsnGlyGlyAspTyrIleGlySer                              100105110                                                                     ATAGACGAGCCTAGTACAACAAATCCACTCGAAAAGCATCATGGACAA384                           IleAspGluProSerThrThrAsnProLeuGluLysHisHisGlyGln                              115120125                                                                     AGGTATGTATATTCAGGGCTTTATTATATTCAATCGTGGAGTCTAAGA432                           ArgTyrValTyrSerGlyLeuTyrTyrIleGlnSerTrpSerLeuArg                              130135140                                                                     GATTTACCAAAGAAGTTTTATTCAGGTTACTATGGATATGCGTATTAC480                           AspLeuProLysLysPheTyrSerGlyTyrTyrGlyTyrAlaTyrTyr                              145150155160                                                                  TTTGGCAAGGAAACAGCCACTACATTACCTGTAAATGGCGAAGCAACG528                           PheGlyLysGluThrAlaThrThrLeuProValAsnGlyGluAlaThr                              165170175                                                                     TATAAAGGAACTTGGGATTTCATCACTGCAACTAGAAATGGCAAAAGT576                           TyrLysGlyThrTrpAspPheIleThrAlaThrArgAsnGlyLysSer                              180185190                                                                     TATTCTTTGTTAAGTAATAACCGACAAGCTTATTCCAAACGTAGTGCA624                           TyrSerLeuLeuSerAsnAsnArgGlnAlaTyrSerLysArgSerAla                              195200205                                                                     ATTCCAGAAGACATTGATTTAGAAAATGATCCAAAGAATGGTGAGACG672                           IleProGluAspIleAspLeuGluAsnAspProLysAsnGlyGluThr                              210215220                                                                     AGATTAACTAGTGAATTTACTGTGAATTTTGGTACGAAAAAGCTCACA720                           ArgLeuThrSerGluPheThrValAsnPheGlyThrLysLysLeuThr                              225230235240                                                                  GGTGGACTTTATTACCATTTACGTAAAACAAATGCTAATGAAAACCAA768                           GlyGlyLeuTyrTyrHisLeuArgLysThrAsnAlaAsnGluAsnGln                              245250255                                                                     AATAGAAAACATAAACTCTACAATCTAGAAGCTGATGTGTATAGCAAC816                           AsnArgLysHisLysLeuTyrAsnLeuGluAlaAspValTyrSerAsn                              260265270                                                                     CGATTCAGAGGTAAAGTAAAGCCAACCAAAGAGTCTTCTGAAGAACAT864                           ArgPheArgGlyLysValLysProThrLysGluSerSerGluGluHis                              275280285                                                                     CCCTTTACCAGCGAGGGAACATTAGAAGGTGGTTTTTATGGGCCTAAT912                           ProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsn                              290295300                                                                     GCTGAAGAACTAGGGGGAAAATTTTTAGCTAGCGATAAAAAAGTTTTT960                           AlaGluGluLeuGlyGlyLysPheLeuAlaSerAspLysLysValPhe                              305310315320                                                                  GGGGTATTTAGTGCCAAAGAACAGCAAGAAACGGAAGAAAACAAAAAA1008                          GlyValPheSerAlaLysGluGlnGlnGluThrGluGluAsnLysLys                              325330335                                                                     TTACTCAAAGAAACCTTAATTGATGGCAAGCTAACTACTTTCTCTACT1056                          LeuLeuLysGluThrLeuIleAspGlyLysLeuThrThrPheSerThr                              340345350                                                                     AAAAAAACCAATGCAACAACCGATGCAACAACCAGTACAACAACCAGT1104                          LysLysThrAsnAlaThrThrAspAlaThrThrSerThrThrThrSer                              355360365                                                                     ACAGCAACCAATGCAACAGCCGATGCAGAAAACTTTACGACAAAAGAT1152                          ThrAlaThrAsnAlaThrAlaAspAlaGluAsnPheThrThrLysAsp                              370375380                                                                     ATATCAAGTTTTGGTGAAGCTGATTATCTTTTAATTGATAATTACCCT1200                          IleSerSerPheGlyGluAlaAspTyrLeuLeuIleAspAsnTyrPro                              385390395400                                                                  GTTCCTCTTTTACCTGAAAATACTAATGATTTCATAAGCAGTAAGCAC1248                          ValProLeuLeuProGluAsnThrAsnAspPheIleSerSerLysHis                              405410415                                                                     CATGAGGTAGGAGGTAAACACTATAAAGTGGAAGCATGTTGCAAGAAT1296                          HisGluValGlyGlyLysHisTyrLysValGluAlaCysCysLysAsn                              420425430                                                                     CTAAGCTATGTGAAATTTGGTATATATTATGAGGATAATGAGAAGAAC1344                          LeuSerTyrValLysPheGlyIleTyrTyrGluAspAsnGluLysAsn                              435440445                                                                     ACCAAAATTGAAACAGAACAATACCACCAATTTTTGTTAGGTCTCCGT1392                          ThrLysIleGluThrGluGlnTyrHisGlnPheLeuLeuGlyLeuArg                              450455460                                                                     ACTCCCAGTTCTCAAATTCCTGCAACGGGAAACGTGAAATATCGCGGT1440                          ThrProSerSerGlnIleProAlaThrGlyAsnValLysTyrArgGly                              465470475480                                                                  AGTTGGTTTGGTTATATTGGTGATGACAAGACATCTTACTCCACTACT1488                          SerTrpPheGlyTyrIleGlyAspAspLysThrSerTyrSerThrThr                              485490495                                                                     GGAGATAAAAATGCTCTCGCCGAGTTTGATGTAAATTTTACCGATAAA1536                          GlyAspLysAsnAlaLeuAlaGluPheAspValAsnPheThrAspLys                              500505510                                                                     AAGCTAACAGGCGAATTAAAACGAGCCGATAATCAAAATACCGTATTT1584                          LysLeuThrGlyGluLeuLysArgAlaAspAsnGlnAsnThrValPhe                              515520525                                                                     AGAATTAATGCAGACTTTAAAAATAATGATAATGCCTTCAAAGGTACA1632                          ArgIleAsnAlaAspPheLysAsnAsnAspAsnAlaPheLysGlyThr                              530535540                                                                     GCAACCGCAGAAAATTTTGTAATAGATGGTAACAATAGTCAAACTGGA1680                          AlaThrAlaGluAsnPheValIleAspGlyAsnAsnSerGlnThrGly                              545550555560                                                                  AATACCCAAATTAATATTAAAACTGAAGTAAATGGGGCATTTTATGGT1728                          AsnThrGlnIleAsnIleLysThrGluValAsnGlyAlaPheTyrGly                              565570575                                                                     CCGAACGCTACAGAATTAGGCGGTTATTTCACTTATAACGGAAAAAAT1776                          ProAsnAlaThrGluLeuGlyGlyTyrPheThrTyrAsnGlyLysAsn                              580585590                                                                     CCTACAGATAAAAATTCTGAAAGTTCCTCAACCGTACCTTCACCACCC1824                          ProThrAspLysAsnSerGluSerSerSerThrValProSerProPro                              595600605                                                                     AATTCACCAAATGCAAGAGCTGCAGTTGTCTTTGGTGCTAAAAAACAA1872                          AsnSerProAsnAlaArgAlaAlaValValPheGlyAlaLysLysGln                              610615620                                                                     GTAGAAAAAAACAACAAGTAAAAACAACCAAGTAATGGAATACTAAAA1920                          ValGluLysAsnAsnLys                                                            625630                                                                        ATGACTAAAAAAGCTTCTAGAAGCCGAATTC1951                                           (2) INFORMATION FOR SEQ ID NO: 113:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 630 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:                                    MetLysSerValProLeuIleSerGlyGlyLeuSerLeuLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlyGlySerPheAspValAspAspValSerAsn                              202530                                                                        ProSerSerSerLysProArgTyrGlnAspAspThrSerSerGlnArg                              354045                                                                        ThrLysSerAsnLeuGluLysLeuSerIleProSerLeuGlyGlyGly                              505560                                                                        MetLysLeuValAlaGlnAsnLeuSerGlyAsnLysGluProSerPhe                              65707580                                                                      LeuAsnGlyAsnAspTyrMetIlePheSerSerArgSerThrIleLys                              859095                                                                        AspAspValGluAsnAsnAsnThrAsnGlyGlyAspTyrIleGlySer                              100105110                                                                     IleAspGluProSerThrThrAsnProLeuGluLysHisHisGlyGln                              115120125                                                                     ArgTyrValTyrSerGlyLeuTyrTyrIleGlnSerTrpSerLeuArg                              130135140                                                                     AspLeuProLysLysPheTyrSerGlyTyrTyrGlyTyrAlaTyrTyr                              145150155160                                                                  PheGlyLysGluThrAlaThrThrLeuProValAsnGlyGluAlaThr                              165170175                                                                     TyrLysGlyThrTrpAspPheIleThrAlaThrArgAsnGlyLysSer                              180185190                                                                     TyrSerLeuLeuSerAsnAsnArgGlnAlaTyrSerLysArgSerAla                              195200205                                                                     IleProGluAspIleAspLeuGluAsnAspProLysAsnGlyGluThr                              210215220                                                                     ArgLeuThrSerGluPheThrValAsnPheGlyThrLysLysLeuThr                              225230235240                                                                  GlyGlyLeuTyrTyrHisLeuArgLysThrAsnAlaAsnGluAsnGln                              245250255                                                                     AsnArgLysHisLysLeuTyrAsnLeuGluAlaAspValTyrSerAsn                              260265270                                                                     ArgPheArgGlyLysValLysProThrLysGluSerSerGluGluHis                              275280285                                                                     ProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsn                              290295300                                                                     AlaGluGluLeuGlyGlyLysPheLeuAlaSerAspLysLysValPhe                              305310315320                                                                  GlyValPheSerAlaLysGluGlnGlnGluThrGluGluAsnLysLys                              325330335                                                                     LeuLeuLysGluThrLeuIleAspGlyLysLeuThrThrPheSerThr                              340345350                                                                     LysLysThrAsnAlaThrThrAspAlaThrThrSerThrThrThrSer                              355360365                                                                     ThrAlaThrAsnAlaThrAlaAspAlaGluAsnPheThrThrLysAsp                              370375380                                                                     IleSerSerPheGlyGluAlaAspTyrLeuLeuIleAspAsnTyrPro                              385390395400                                                                  ValProLeuLeuProGluAsnThrAsnAspPheIleSerSerLysHis                              405410415                                                                     HisGluValGlyGlyLysHisTyrLysValGluAlaCysCysLysAsn                              420425430                                                                     LeuSerTyrValLysPheGlyIleTyrTyrGluAspAsnGluLysAsn                              435440445                                                                     ThrLysIleGluThrGluGlnTyrHisGlnPheLeuLeuGlyLeuArg                              450455460                                                                     ThrProSerSerGlnIleProAlaThrGlyAsnValLysTyrArgGly                              465470475480                                                                  SerTrpPheGlyTyrIleGlyAspAspLysThrSerTyrSerThrThr                              485490495                                                                     GlyAspLysAsnAlaLeuAlaGluPheAspValAsnPheThrAspLys                              500505510                                                                     LysLeuThrGlyGluLeuLysArgAlaAspAsnGlnAsnThrValPhe                              515520525                                                                     ArgIleAsnAlaAspPheLysAsnAsnAspAsnAlaPheLysGlyThr                              530535540                                                                     AlaThrAlaGluAsnPheValIleAspGlyAsnAsnSerGlnThrGly                              545550555560                                                                  AsnThrGlnIleAsnIleLysThrGluValAsnGlyAlaPheTyrGly                              565570575                                                                     ProAsnAlaThrGluLeuGlyGlyTyrPheThrTyrAsnGlyLysAsn                              580585590                                                                     ProThrAspLysAsnSerGluSerSerSerThrValProSerProPro                              595600605                                                                     AsnSerProAsnAlaArgAlaAlaValValPheGlyAlaLysLysGln                              610615620                                                                     ValGluLysAsnAsnLys                                                            625630                                                                        (2) INFORMATION FOR SEQ ID NO: 114:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 1955 base pairs                                                   (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: CDS                                                             (B) LOCATION: 1..1893                                                         (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114:                                    ATGAAATCTGTACCTCTTATCTCTGGTGGACTTTCCTTTTTACTAAGT48                            MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        GCTTGTAGCGGAGGGGGGTCTTTTGATGTAGATAACGTCTCTAATACC96                            AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnThr                              202530                                                                        CCCTCTTCTAAACCACGTTATCAAGACGATACCTCGAATCAAAGAACA144                           ProSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArgThr                              354045                                                                        AAATCTAAATTGGAAAAGTTGTCCATTCCTTCTTTAGGAGGAGGGATG192                           LysSerLysLeuGluLysLeuSerIleProSerLeuGlyGlyGlyMet                              505560                                                                        AAGTTAGTTGTGCAAAATTTTGCTGGTGCTAAAGAACCTAGTTTCTTA240                           LysLeuValValGlnAsnPheAlaGlyAlaLysGluProSerPheLeu                              65707580                                                                      AATGAAAATGACTATATATCATATTTTTCCTCACTTTCTATGATTAAA288                           AsnGluAsnAspTyrIleSerTyrPheSerSerLeuSerMetIleLys                              859095                                                                        GATGATGTTGAAAATAACAATAAAAATAAGGATACTCCAATTGGCTCA336                           AspAspValGluAsnAsnAsnLysAsnLysAspThrProIleGlySer                              100105110                                                                     ATAGACGAGCCTAGAGCACCAAATTCAAACGAAAATCATCAAAATCAT384                           IleAspGluProArgAlaProAsnSerAsnGluAsnHisGlnAsnHis                              115120125                                                                     CATGGACAGCAATATGTATATTCGGGTCTTTATTATATTCCATCGTGG432                           HisGlyGlnGlnTyrValTyrSerGlyLeuTyrTyrIleProSerTrp                              130135140                                                                     CGTCTAATAAATTTACCAAATAAGTTTTATTCAGGTTACTATGGATAT480                           ArgLeuIleAsnLeuProAsnLysPheTyrSerGlyTyrTyrGlyTyr                              145150155160                                                                  GCGTATTACTTTGGCAAGCAAACTGCCACTACATTACCTGTAAATGGC528                           AlaTyrTyrPheGlyLysGlnThrAlaThrThrLeuProValAsnGly                              165170175                                                                     GAAGCAACGTATAAAGGAACTTGGAGCTTCATCACCGCAACTGAAAGA576                           GluAlaThrTyrLysGlyThrTrpSerPheIleThrAlaThrGluArg                              180185190                                                                     GGCAAAAATTATTCTTTGTTCAATAATAGAGGTCAAGCTTATTCTCGA624                           GlyLysAsnTyrSerLeuPheAsnAsnArgGlyGlnAlaTyrSerArg                              195200205                                                                     CGTAGTGCTACTCCAGGAGATATTGATTTAGAAAACGGTGACGCAGGC672                           ArgSerAlaThrProGlyAspIleAspLeuGluAsnGlyAspAlaGly                              210215220                                                                     TTAACAAGTGAATTTACTGTCAATTTTGGTACAAAAAAGCTCACTGGA720                           LeuThrSerGluPheThrValAsnPheGlyThrLysLysLeuThrGly                              225230235240                                                                  GAACCTTATTATAATGAAAGGGAAACAAATCTTAATCAATCAAAAGAT768                           GluProTyrTyrAsnGluArgGluThrAsnLeuAsnGlnSerLysAsp                              245250255                                                                     AGAAAACATAAACTCTACGATCTAGAAGCTGATGTGTATAGCAACCGA816                           ArgLysHisLysLeuTyrAspLeuGluAlaAspValTyrSerAsnArg                              260265270                                                                     TTCAGAGGTACAGTAAAGCCAACCAAAAAAGAGTCTTCTGAAGAACAT864                           PheArgGlyThrValLysProThrLysLysGluSerSerGluGluHis                              275280285                                                                     CCCTTTACCAGCGAGGGAACATTAGAAGGTGGTTTTTATGGGCCTAAT912                           ProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsn                              290295300                                                                     GCTGAAGAACTAGGGGGAAAATTTTTAGCTAGCGATAAAAAAGTTTTT960                           AlaGluGluLeuGlyGlyLysPheLeuAlaSerAspLysLysValPhe                              305310315320                                                                  GGGGTATTTAGTGCCAAAGAAACGGAAGAAAAACCAAAATTACCCAAA1008                          GlyValPheSerAlaLysGluThrGluGluLysProLysLeuProLys                              325330335                                                                     GAAACCTTAATTGATGGCAAGCTAACTACTTTCTCTAAAACAACCGAT1056                          GluThrLeuIleAspGlyLysLeuThrThrPheSerLysThrThrAsp                              340345350                                                                     ACAACAACCAATAAAACAACCAGTGCAAAAACCAATACAGAAAACTTT1104                          ThrThrThrAsnLysThrThrSerAlaLysThrAsnThrGluAsnPhe                              355360365                                                                     ACGACAAAAGATATACCAAGTTTTGGTGAAGCTGATTATCTTTTAATT1152                          ThrThrLysAspIleProSerPheGlyGluAlaAspTyrLeuLeuIle                              370375380                                                                     GATAATTACCCTATTCCGCTTTTACCTGAGAGTGGTGATTTCATAAGT1200                          AspAsnTyrProIleProLeuLeuProGluSerGlyAspPheIleSer                              385390395400                                                                  AGTAAGCACCATGAGGTAGGAGGTAAACGCTATAAAGTGGAAGCATGT1248                          SerLysHisHisGluValGlyGlyLysArgTyrLysValGluAlaCys                              405410415                                                                     TGCAAGAATCTATGCTATGTGAAATTTGGTATGTATTATGAGGATAAA1296                          CysLysAsnLeuCysTyrValLysPheGlyMetTyrTyrGluAspLys                              420425430                                                                     GAGAACAACAAAAATGAAACAGACAAAGAAAAAGAAAAACAAACGACA1344                          GluAsnAsnLysAsnGluThrAspLysGluLysGluLysGlnThrThr                              435440445                                                                     ACATCTATCAAGACTTATTATCAATTCTTATTAGGTCTCCGGACTCCC1392                          ThrSerIleLysThrTyrTyrGlnPheLeuLeuGlyLeuArgThrPro                              450455460                                                                     AGTTCTGAAATTCCTAAAATGGGAAACGTGACATATCGCGGTAGTTGG1440                          SerSerGluIleProLysMetGlyAsnValThrTyrArgGlySerTrp                              465470475480                                                                  TTTGGTTATATTGGTGATGACAAGACATCTTACTCCGCTACAGGAGAT1488                          PheGlyTyrIleGlyAspAspLysThrSerTyrSerAlaThrGlyAsp                              485490495                                                                     AAACGACAAGATAAAAATGCTCCCGCCGAGTTTAATGCTGATTTTAAC1536                          LysArgGlnAspLysAsnAlaProAlaGluPheAsnAlaAspPheAsn                              500505510                                                                     AATAAAAAGCTAACAGGCACATCAAAACGACACGATAATCAAAATCCC1584                          AsnLysLysLeuThrGlyThrSerLysArgHisAspAsnGlnAsnPro                              515520525                                                                     GTGTTTAACATTAAGGCAACCTTTCAAAATGGTCGGAATGACTTTGAA1632                          ValPheAsnIleLysAlaThrPheGlnAsnGlyArgAsnAspPheGlu                              530535540                                                                     GGTACAGCAACCGCAGAAAATTTTGTAATAGATGGTAAAGATAGTCAA1680                          GlyThrAlaThrAlaGluAsnPheValIleAspGlyLysAspSerGln                              545550555560                                                                  GGAAATACCCCAATTAATATTACAACTAAAGTAAACGGGGCATTTTAT1728                          GlyAsnThrProIleAsnIleThrThrLysValAsnGlyAlaPheTyr                              565570575                                                                     GGACCTGATGCTTCTGAATTAGGCGGTTATTTCACCTATAACGGAAAA1776                          GlyProAspAlaSerGluLeuGlyGlyTyrPheThrTyrAsnGlyLys                              580585590                                                                     GACACTATAACTAAAAATACTGAAAGTTCCTCAACCGTACCTTCACCA1824                          AspThrIleThrLysAsnThrGluSerSerSerThrValProSerPro                              595600605                                                                     CCCAATTCACCAAATGCAAGAGCTGCAGTTGTGTTTGGAGCTAAAAAA1872                          ProAsnSerProAsnAlaArgAlaAlaValValPheGlyAlaLysLys                              610615620                                                                     CAAGTAGAAACAACCAACAAGTAGAAAAAAACAAATAATGGAATACTAAAA1923                       GlnValGluThrThrAsnLys                                                         625630                                                                        ATGACTAAAAAAGCTTCTAGAAAGCCGAATTC1955                                          (2) INFORMATION FOR SEQ ID NO: 115:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 631 amino acids                                                   (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115:                                    MetLysSerValProLeuIleSerGlyGlyLeuSerPheLeuLeuSer                              151015                                                                        AlaCysSerGlyGlyGlySerPheAspValAspAsnValSerAsnThr                              202530                                                                        ProSerSerLysProArgTyrGlnAspAspThrSerAsnGlnArgThr                              354045                                                                        LysSerLysLeuGluLysLeuSerIleProSerLeuGlyGlyGlyMet                              505560                                                                        LysLeuValValGlnAsnPheAlaGlyAlaLysGluProSerPheLeu                              65707580                                                                      AsnGluAsnAspTyrIleSerTyrPheSerSerLeuSerMetIleLys                              859095                                                                        AspAspValGluAsnAsnAsnLysAsnLysAspThrProIleGlySer                              100105110                                                                     IleAspGluProArgAlaProAsnSerAsnGluAsnHisGlnAsnHis                              115120125                                                                     HisGlyGlnGlnTyrValTyrSerGlyLeuTyrTyrIleProSerTrp                              130135140                                                                     ArgLeuIleAsnLeuProAsnLysPheTyrSerGlyTyrTyrGlyTyr                              145150155160                                                                  AlaTyrTyrPheGlyLysGlnThrAlaThrThrLeuProValAsnGly                              165170175                                                                     GluAlaThrTyrLysGlyThrTrpSerPheIleThrAlaThrGluArg                              180185190                                                                     GlyLysAsnTyrSerLeuPheAsnAsnArgGlyGlnAlaTyrSerArg                              195200205                                                                     ArgSerAlaThrProGlyAspIleAspLeuGluAsnGlyAspAlaGly                              210215220                                                                     LeuThrSerGluPheThrValAsnPheGlyThrLysLysLeuThrGly                              225230235240                                                                  GluProTyrTyrAsnGluArgGluThrAsnLeuAsnGlnSerLysAsp                              245250255                                                                     ArgLysHisLysLeuTyrAspLeuGluAlaAspValTyrSerAsnArg                              260265270                                                                     PheArgGlyThrValLysProThrLysLysGluSerSerGluGluHis                              275280285                                                                     ProPheThrSerGluGlyThrLeuGluGlyGlyPheTyrGlyProAsn                              290295300                                                                     AlaGluGluLeuGlyGlyLysPheLeuAlaSerAspLysLysValPhe                              305310315320                                                                  GlyValPheSerAlaLysGluThrGluGluLysProLysLeuProLys                              325330335                                                                     GluThrLeuIleAspGlyLysLeuThrThrPheSerLysThrThrAsp                              340345350                                                                     ThrThrThrAsnLysThrThrSerAlaLysThrAsnThrGluAsnPhe                              355360365                                                                     ThrThrLysAspIleProSerPheGlyGluAlaAspTyrLeuLeuIle                              370375380                                                                     AspAsnTyrProIleProLeuLeuProGluSerGlyAspPheIleSer                              385390395400                                                                  SerLysHisHisGluValGlyGlyLysArgTyrLysValGluAlaCys                              405410415                                                                     CysLysAsnLeuCysTyrValLysPheGlyMetTyrTyrGluAspLys                              420425430                                                                     GluAsnAsnLysAsnGluThrAspLysGluLysGluLysGlnThrThr                              435440445                                                                     ThrSerIleLysThrTyrTyrGlnPheLeuLeuGlyLeuArgThrPro                              450455460                                                                     SerSerGluIleProLysMetGlyAsnValThrTyrArgGlySerTrp                              465470475480                                                                  PheGlyTyrIleGlyAspAspLysThrSerTyrSerAlaThrGlyAsp                              485490495                                                                     LysArgGlnAspLysAsnAlaProAlaGluPheAsnAlaAspPheAsn                              500505510                                                                     AsnLysLysLeuThrGlyThrSerLysArgHisAspAsnGlnAsnPro                              515520525                                                                     ValPheAsnIleLysAlaThrPheGlnAsnGlyArgAsnAspPheGlu                              530535540                                                                     GlyThrAlaThrAlaGluAsnPheValIleAspGlyLysAspSerGln                              545550555560                                                                  GlyAsnThrProIleAsnIleThrThrLysValAsnGlyAlaPheTyr                              565570575                                                                     GlyProAspAlaSerGluLeuGlyGlyTyrPheThrTyrAsnGlyLys                              580585590                                                                     AspThrIleThrLysAsnThrGluSerSerSerThrValProSerPro                              595600605                                                                     ProAsnSerProAsnAlaArgAlaAlaValValPheGlyAlaLysLys                              610615620                                                                     GlnValGluThrThrAsnLys                                                         625630                                                                        (2) INFORMATION FOR SEQ ID NO: 116:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 100 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:                                    TCTAACTTGACATTATTACAAAAAAAGATCAATAATGCGAATTATTATCAATTTTGTATG60                AGTATATAATTCTATGAAATCTGTACCTCTTATCTCTGGT100                                   (2) INFORMATION FOR SEQ ID NO: 117:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 100 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117:                                    TCTAACTTGACATTATTACAAAAAAAGATCAATAATGCGAATTATTATCAATTTTGTATG60                AGTATATAATTCTATGAAATCTGTACCTCTTATCTCTGGT100                                   (2) INFORMATION FOR SEQ ID NO: 118:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 99 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118:                                    TCTAAGTTGACATTATTACAAAAAAAGAACAATAATGCGAATTATTATCAATTTTGTATA60                AGTATTAATTCTATGAAATCTGTACCTCTTATCTCTGGT99                                     (2) INFORMATION FOR SEQ ID NO: 119:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 100 base pairs                                                    (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 119:                                    TCTAAGTTGACATTATTACAAAAAAAGAACAATAATGCGAATTATTATCAATTTTGTATA60                AGAATATAATTCTATGAAATCTGTACCTCTTATCTCTGGT100                                   (2) INFORMATION FOR SEQ ID NO: 120:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120:                                    GGATCCATATGAAATCTGTACCTCTTATCTCTGGT35                                         (2) INFORMATION FOR SEQ ID NO: 121:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 61 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121:                                    GTAGAAACAACCAAATAATGGAATACTAAAAATGACTAAAAAACCCTATTTTCGCCTAAG60                T61                                                                           (2) INFORMATION FOR SEQ ID NO: 122:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 61 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122:                                    GTAGAAACAACCAAATAATGGAATACTAAAAATGACTAAAAAACCCTATTTTCGCCTAAG60                T61                                                                           (2) INFORMATION FOR SEQ ID NO: 123:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 61 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123:                                    GTAGAAACAACCAAGTAATGGAATACTAAAAATGACTAAAAAACCCTATTTTCGCCTAAG60                T61                                                                           (2) INFORMATION FOR SEQ ID NO: 124:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 78 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124:                                    GTAGAAACAACCAACAAGTAAAAACAACCAAGTAATGGAATACTAAAAATGACTAAAAAA60                CCCTATTTTCGCCTAAGT78                                                          (2) INFORMATION FOR SEQ ID NO: 125:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 43 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125:                                    GTAGAAACAACCAAATAATGGAATACTAAAAATGACTAAAAAA43                                 (2) INFORMATION FOR SEQ ID NO: 126:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 60 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126:                                    GTAGAAACAACCAACAAGTAAAAACAACCAAGTAATGGAATACTAAAAATGACTAAAAAA60                (2) INFORMATION FOR SEQ ID NO: 127:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 60 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127:                                    GTAGAAAAAAACAACTAGTAAAAACAACCAAGTAATGGAATACTAAAAATGACTAAAAAA60                (2) INFORMATION FOR SEQ ID NO: 128:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 60 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128:                                    GTAGAAACAACCAACAAGTAGAAAAAAACAAATAATGGAATACTAAAAATGACTAAAAAA60                (2) INFORMATION FOR SEQ ID NO: 129:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 129:                                    TCTAGAAGCTTTTTTAGTCATTTTTAGTATTCCAT35                                         (2) INFORMATION FOR SEQ ID NO: 130:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 58 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 130:                                    TATGTGTTCTGGTGGTGGTTCTTTCGACGTTGACAACGTTTCTAACACTCCCTCTTCT58                  (2) INFORMATION FOR SEQ ID NO: 131:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 59 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131:                                    ACACAAGACCACCACCAAGAAAGCTGCAACTGTTGCAAAGATTGTGAGGGAGAAGATTT59                 (2) INFORMATION FOR SEQ ID NO: 132:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 132:                                    AsnProAlaSerThrThrAsnLysAsp                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO: 133:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 17 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133:                                    AsnProAlaSerThrThrSerLeuGluGlyGlyPheTyrGlyProLys                              151015                                                                        Asp                                                                           (2) INFORMATION FOR SEQ ID NO: 134:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 134:                                    AsnProAlaSerThrThrSerLeuGluGlyGlyPheTyrGlyLysAsp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 135:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 16 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 135:                                    AsnProAlaSerThrThrLeuGluGlyGlyPheTyrGlyProLysAsp                              151015                                                                        (2) INFORMATION FOR SEQ ID NO: 136:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136:                                    AsnProAlaSerThrThrLeuGluGlyGlyPheTyrGlyLysAsp                                 151015                                                                        (2) INFORMATION FOR SEQ ID NO: 137:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 35 base pairs                                                     (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 137:                                    TCTAGAAGCTTTTTTAGTCATTTTTAGTATTCCAT35                                         (2) INFORMATION FOR SEQ ID NO: 138:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 138:                                    MetThrLysLys                                                                  1                                                                             (2) INFORMATION FOR SEQ ID NO: 139:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 139:                                    GluGlnValLeuAsn                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO: 140:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 140:                                    AspIleArgAspLeuThrArgTyrAsp                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO: 141:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 18 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 141:                                    GlyAlaIleAsnGluIleGluTyrGluAsnValLysAlaValGluIle                              151015                                                                        SerLys                                                                        (2) INFORMATION FOR SEQ ID NO: 142:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 5 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 142:                                    ValTyrAsnLeuPhe                                                               15                                                                            (2) INFORMATION FOR SEQ ID NO: 143:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 143:                                    LeuAsnTyrArgTyrValThrTrpGlu                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO: 144:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 144:                                    CysSerGlyGlyGlyGlySerPheAsp                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO: 145:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 9 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 145:                                    CysLeuGlyGlyGlyGlySerPheAsp                                                   15                                                                            (2) INFORMATION FOR SEQ ID NO: 146:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 146:                                    LeuSerGlyGlyPhePheGlyPro                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO: 147:                                           (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 147:                                    MetLysSerValProLeuIleSerGlySer                                                1510                                                                          __________________________________________________________________________

What we claim is:
 1. A method of producing an isolated and purified Tbp1or Tbp2 protein of a strain of Haemophilus influenzae, comprising thesteps of:(a) providing a recombinant host expressing, in inclusionbodies, a Tbp1 or Tbp2 protein, but not both, of a strain of Haemophilusinfluenzae; (b) growing said host to provide a cell mass wherein saidTbp1 or Tbp2 protein is present in inclusion bodies; (c) disrupting thecell mass to provide a cell lysate; (d) fractionating the cell lysate toprovide a first supernatant and a first pellet, the first supernatantcomprising substantially a large proportion of soluble host proteins;(e) separating said first supernatant from said first pellet; (f)selectively extracting the first pellet to remove substantially allsoluble host proteins and host membrane proteins therefrom to provide asecond supernatant and an extracted pellet containing the inclusionbodies; (g) separating said second supernatant from said extractedpellet; (h) solubilizing the extracted pellet to provide a solubilizedextract; and (i) fractionating the solubilized extract to provide a Tbp1or Tbp2 protein containing fraction.
 2. The method of claim 1 whereinthe cell lysate is fractionated by centrifugation thereof.
 3. The methodof claim 2 wherein the step of selectively extracting the first pelletcomprises at least one detergent extraction.
 4. The method of claim 3wherein the solubilized extract is fractionated by gel filtration toprovide said Tbp1 or Tbp2 protein containing fraction.
 5. The method ofclaim 4 including subsequently dialyzing the Tbp1 or Tbp2 proteincontaining fraction to remove at least said detergent to provide afurther purified solution of Tbp1 or Tbp2 protein.